2-Oxo-Thiazole Derivatives as A2A Inhibitors and Compounds for Use in the Treatment of Cancers

ABSTRACT

The present invention relates to compounds of Formula Ior pharmaceutically acceptable salts or solvates thereof. The invention further relates to the use of the compounds of Formula I as A2A inhibitors. The invention also relates to the use of the compounds of Formula I for the treatment and/or prevention of cancer. The invention also relates to a process for manufacturing compounds of Formula I.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/993,897, filed on Aug. 14, 2020, which is a continuation of U.S.patent application Ser. No. 16/354,022, filed on Mar. 14, 2019, now U.S.Pat. No. 10,995,101, which is a continuation of International PatentApplication No. PCT/EP2018/058301, filed Mar. 30, 2018, which claimspriority to European Patent Application No. 17163781.2, filed Mar. 30,2017, European Patent Application No. 17194084.4, filed Sep. 29, 2017,U.S. Provisional Application No. 62/565,281, filed Sep. 29, 2017, andArgentinian Patent Application No. P 20180100778, filed Mar. 28, 2018,the entire disclosure of each of which is incorporated by referenceherein for all purposes.

FIELD OF INVENTION

The present invention relates to novel thiocarbamate derivatives,including pharmaceutically acceptable salts and solvates thereof.Compounds of the invention are inhibitors of adenosine A2A receptor andare useful as therapeutic compounds, particularly in the treatmentand/or prevention of cancers.

BACKGROUND OF INVENTION

Many of the immunosuppressive mechanisms in tumors are common tophysiological immunoregulation in normal tissues. Such immunoregulationis very important in keeping the immune system under control in order toblock a self-reactive immune response and to prevent an ongoing immuneresponse from causing critical tissue damage. The lack of physiologicalimmunoregulation often results in overwhelming immune activation thataccompanies autoimmunity. For example, CTLA-4 is a physiologicalmechanism that negatively regulates T cell activity by blocking acostimulatory signal through CD28-B7 interaction. The lack of CTLA4causes non-specific T cell activation, and CTLA-4-deficient mice die inseveral weeks with massive lymphocytic tissue infiltration. PD-1 alsoprovides a T cell inhibitory signal upon interaction with its ligands,PD-L1 and PD-L2. Deficiency of PD-1 in mice is known to cause varioustypes of autoimmune disorders depending on the genetic strains.

Besides cell surface transducers of immunosuppressive signal, e.g.,CTLA-4 and PD-1, immunosuppression in the tumor microenvironmentinvolves anti-inflammatory cytokines (IL-10, TGF-β), enzymes(indoleamine-2,3-dioxygenase), and professional immunoregulatory cells(regulatory T cells, myeloid-derived suppressor cells MDSCs).

These immunosuppressive mechanisms play an important role in controllingimmune response in normal tissues. Since tumors take advantage of suchphysiological immunoregulatory mechanisms to protect their tissue fromimmune attack, these mechanisms intended to prevent inflammatorycomplication, now turn out to be major obstacles hampering spontaneouscancer regression and immunological cancer treatment. The identificationof immunosuppressive mechanisms in tumors pointed out molecular targetsto restore the antitumor immune response. Thus, these negativeimmunoregulatory mechanisms, so-called immune checkpoints, became afocus in drug discovery. Antibodies against PD1, PDL1 or CTLA4 have beenapproved as anticancer therapies on a large number of indications, suchas Metastatic Melanoma, Non-Small Cell Lung Cancer, Renal CellCarcinoma, Hodgkin's Lymphoma, Head and Neck Cancer, UrothelialCarcinoma, Hepatocellular Carcinoma, as well as treatment of forpatients with solid tumors that have one of two specific geneticfeatures known as mismatch repair deficiency and high microsatelliteinstability (irrespective of cancer type).

Extracellular adenosine has been known as an inhibitor of immunefunctions. While intracellular adenosine is involved in energymetabolism, nucleic acid metabolism, and the methionine cycle,extracellular adenosine plays an important role in intercellularsignaling. Its signal is transmitted by G protein-coupled adenosinereceptors on the cell surface, and it affects diverse physiologicalfunctions including neurological, cardiovascular, and immunologicalsystems.

Tumors contain high levels of extracellular adenosine, suggesting thattumor cells may benefit from its immunosuppressive effect and catabolicenergy production (Allard et al., Curr. Opin. Pharmacol., 2016, 29,7-16; Otta A., Frontiers in Immunology, 2016, 7: 109). This high levelof extracellular adenosine is probably due to overexpression of theenzyme CD73, which is responsible for production of extracellularadenosine. CD73 is overexpressed by a large number of tumors, with allthe following tumors expressing medium or high levels of CD73 in >50% oftumor surface by immunohistochemistry (www.proteinatlas.org): Breast,Carcinoid, Cervical, Colorectal, Endometrial, Glioma, Head and Neck,Liver, Lung, Melanoma, Ovarian, Pancreatic, Prostate, Renal, Gastric,Thyroid, Urothelial.

Of the four known types of adenosine receptors, A2A adenosine receptor(A2AR) is the predominantly expressed subtype in most immune cells.Stimulation of A2AR generally provides an immunosuppressive signal thatinhibits activities of T cells (proliferation, cytokine production,cytotoxicity), NK cells (cytotoxicity), NKT cells (cytokine production,CD40L upregulation), macrophages/dendritic cells (antigen presentation,cytokine production), and neutrophils (oxidative burst). The presence ofhigh levels of extracellular adenosine in tumors was found to play asignificant role in the evasion of antitumor immune response.Especially, it was shown that A2AR-deficient mice could spontaneouslyregress the inoculated tumor, whereas no wild-type mice showed similartumor regression. A2AR antagonists were also beneficial in tumor-bearingwild-type animals. Importantly, depletion of T cells and NK cellsimpaired the retardation of tumor growth by A2AR antagonists, suggestingimprovement of antitumor cellular immune response. Effector functions ofT cells and NK cells are susceptible to A2AR stimulation. In addition,when activated in the presence of A2AR agonist, the effector function ofT cells is persistently impaired even after removal of A2AR agonist.This result suggests that the adenosine-rich environment in tumors mayinduce T cells that are anergic to the tumor cells.

Therefore, given that A2A receptor is expressed in most immune cells andparticularly effector immune cells such as T cells and NK cells andgiven that A2A receptor is engaged in tissues where adenosine isproduced, it is thought that A2A inhibitors can be helpful in all thecancer indications.

Consequently, there is a need for A2A inhibitors able to restore immunefunctions in tumors environment.

Adenosine is known to be an endogenous modulator of a number of otherphysiological functions. For example, at the central nervous system(CNS) level, adenosine in known to induce sedative, anxiolotic andantiepileptic effects level. Thus, A2A inhibitors were previouslydeveloped for the treatment of depression and neurodegenerative diseasessuch as Parkinson's disease or Alzheimer's disease (Pinna A., CNS Drugs,2014, 28, 455). One of the most advanced A2A inhibitors developed forthe treatment of CNS diseases is Preladenant (Hodgson R A et al., J.Pharmacol. Exp. Ther., 2009, 330(1), 294-303; Hauser R A et al., JAMANeurol., 2015, 72(12), 1491-500).

However, such previously developed A2A inhibitors were designed to crossthe blood brain barrier, in order to target A2A receptor in the CNS.

Given the higher level of adenosine in tumors when compared to thebrain, much higher amounts of compounds will be needed to achieve thedesired effect on immune functions restoration for treating cancers.Thus, in order to avoid deleterious side effects, one should provide A2Ainhibitors which have a limited, if any, CNS penetrance, contrary to allpreviously developed A2A inhibitors.

As evidenced in the experimental part below, the Applicant herebyprovides new A2A inhibitors which do not have any significant CNSpenetrance, and which may thus be useful in the treatment of cancers.

SUMMARY

This invention thus relates to a compound of Formula (I)

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein R¹ and R² are as defined below.

According to one embodiment, compounds of Formula (I) are of Formula(Ia)

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein R¹, R^(1′), R^(2′), R^(3′), R^(4′) and R^(5′) are as        defined below.

According to one embodiment, compounds of Formula (Ia) are of Formula(Ia-1)

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein R¹, R^(1′), R^(2′), R^(3′), R^(4′) and R^(5′) are as        defined in Formula (Ia).

According to one embodiment, compounds of Formula (Ia) are of Formulae(Ia-2) or (Ia-3)

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein R¹, R^(2′), R^(3′), R^(4′) and R^(5′) are as defined in        Formula (Ia).

The invention also relates to a pharmaceutical composition comprising acompound according to the invention, or a pharmaceutically acceptablesalt or solvate thereof, and at least one pharmaceutically acceptablecarrier.

The invention further relates to a medicament comprising a compoundaccording to the invention, or a pharmaceutically acceptable salt orsolvate thereof.

The invention also provides a compound according to the invention or apharmaceutically acceptable salt or solvate thereof for use in thetreatment and/or prevention of cancer.

The invention further relates to a compound according to the inventionor a pharmaceutically acceptable salt or solvate thereof for use as A2Ainhibitor.

It is also provided a process for manufacturing a compound of Formula(Ia) according to the invention or a pharmaceutically acceptable salt orsolvate thereof, characterized in that it comprises the coupling betweenamine intermediate of Formula (A)

-   -   wherein X¹, X², R^(1′), R^(2′), R^(3′), R^(4′) and R^(5′) are as        defined in below; and intermediate of Formula (B)

-   -   wherein R¹ is as defined below and Y represents halo,        alkylsulfonyloxy having 1 to 6 carbon atoms or arylsulfonyloxy        having 6 to 10 carbon atoms.

The invention also relates to intermediates of synthesis of Formula (A).

Definitions

In the present invention, the following terms have the followingmeanings:

The term “aldehyde” refers to a group —CHO.

The term “aldehydealkyl” refers to a group -alkyl-CHO wherein alkyl isas herein defined.

The term “alkenyl” refers to unsaturated hydrocarbyl group, which may belinear or branched, comprising one or more carbon-carbon double bonds.Suitable alkenyl groups comprise between 2 and 6 carbon atoms,preferably between 2 and 4 carbon atoms, still more preferably between 2and 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl,2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and itsisomers, 2,4-pentadienyl and the like.

The term “alkenylcarbonyl” refers to a group —(C═O)-alkenyl whereinalkenyl is as herein defined.

The term “alkenylcarbonylalkyl” refers to a group -alkyl-(C═O)-alkenylwherein alkyl and alkenyl are as herein defined.

The term “alkenylcarbonylamino” refers to a group —NH—(C═O)-alkenylwherein alkenyl is as herein defined.

The term “alkenylcarbonylaminoalkyl” refers to a group-alkyl-NH—(C═O)-alkenyl wherein alkyl and alkenyl are as herein defined.

The term “alkoxy” refers to a group —O-alkyl wherein alkyl is as hereindefined.

The term “alkyl” refers to a hydrocarbyl radical of formulaC_(n)H_(2n+1) wherein n is a number greater than or equal to 1.Generally, alkyl groups of this invention comprise from 1 to 8 carbonatoms, more preferably, alkyl groups of this invention comprise from 1to 6 carbon atoms. Alkyl groups may be linear or branched. Suitablealkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyland octyl.

The term “alkylaminoalkyl” refers to a group -alkyl-NH-alkyl whereinalkyl is as herein defined.

The term “alkylaminoalkylaminocarbonyl” refers to a group—(C═O)—NH-alkyl-NH-alkyl wherein alkyl is as herein defined.

The term “(alkylaminoalkyl)(alkyl)aminocarbonyl” refers to a group—(C═O)—NR¹R² wherein R¹ is an alkyl group and R² is a -alkyl-NH-alkylgroup, wherein alkyl is as herein defined.

The term “alkylaminoalkylcarbonyl” refers to a group—(C═O)-alkyl-NH-alkyl wherein alkyl is as herein defined.

The term “alkylcarbonyl” refers to a group —(C═O)-alkyl wherein alkyl isas herein defined.

The term “alkylheteroaryl” refers to any heteroaryl substituted by analkyl group wherein alkyl is as herein defined.

The term “alkyloxycarbonyl” refers to a group —(C═O)—O-alkyl whereinalkyl is as herein defined.

The term “alkylsulfonyl” refers to a group —SO₂-alkyl wherein alkyl isas herein defined.

The term “alkylsulfonealkyl” refers to a group -alkyl-SO₂-alkyl whereinalkyl is as herein defined.

The term “alkylsulfonimidoyl” refers to a group —S(═O)(═NH)-alkylwherein alkyl is as herein defined.

The term “alkylsulfoxide” refers to a group —(S═O)-alkyl wherein alkylis as herein defined.

The term “alkylsulfoxidealkyl” refers to a group -alkyl-SO-alkyl whereinalkyl is as herein defined.

The term “alkyne” refers to a class of monovalent unsaturatedhydrocarbyl groups, wherein the unsaturation arises from the presence ofone or more carbon-carbon triple bonds. Alkynyl groups typically, andpreferably, have the same number of carbon atoms as described above inrelation to alkyl groups. Non-limiting examples of alkynyl groups areethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers,2-hexynyl and its isomers and the like.

The term “alkynealkyl” refers to a group -alkyl-alkyne wherein alkyl andalkyne are as herein defined.

The term “alkynecarbonylalkyl” refers to a group -alkyl-(C═O)-alkynewherein alkyl and alkyne are as herein defined.

The term “amino” refers to a group —NH₂.

The term “aminoalkyl” refers to a group -alkyl-NH₂ wherein alkyl is asherein defined.

The term “aminoalkylaminocarbonyl” refers to a group —(C═O)—NH-alkyl-NH₂wherein alkyl is as herein defined.

The term “aminoalkylcarbonylamino” refers to a group —NH—(C═O)-alkyl-NH₂wherein alkyl is as herein defined.

The term “aminocarbonyl” refers to a group —(C═O)—NH₂.

The term “(aminocarbonylalkyl)(alkyl)amino” refers to a group —NR¹R²wherein R¹ is an alkyl group and R² is a -alkyl-(C═O)—NH₂ group, whereinalkyl is as herein defined.

The term “aminocarbonylalkylamino” refers to a group —NH-alkyl-(C═O)—NH₂wherein alkyl is as herein defined.

The term “aminosulfonyl” refers to a group —SO₂—NH₂.

The term “aryl” refers to a polyunsaturated, aromatic hydrocarbyl grouphaving a single ring (i.e. phenyl) or multiple aromatic rings fusedtogether (e.g. naphtyl), typically containing 5 to 12 atoms; preferably5 to 10; more preferably the aryl is a 5- or 6-membered aryl.Non-limiting examples of aryl comprise phenyl, naphthalenyl.

The term “carbonyl” refers to a group —(C═O)—.

The term “carbonylamino” refers to a group —NH—(C═O)—.

The term “cycloalkyl” refers to a cyclic alkyl group, that is to say, amonovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2cyclic structures. Cycloalkyl includes monocyclic or bicyclichydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbonatoms in the ring and generally, according to this invention comprisefrom 3 to 10, more preferably from 3 to 8 carbon atoms; still morepreferably more preferably the cycloalkyl is a 5- or 6-memberedcycloalkyl. Examples of cycloalkyl groups include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term “cycloalkyloxy” refers to a group —O-cycloalkyl whereincycloalkyl is as herein defined.

The term “dialkylamino” refers to a group —NR¹R² wherein R¹ and R² areboth independently alkyl group as herein defined.

The term “dialkylaminoalkyl” refers to a group -alkyl-NR¹R² wherein R¹and R² are both independently alkyl group, as herein defined.

The term “dialkylaminoalkylaminocarbonyl” refers to a group—(C═O)—NH-alkyl-NR¹R² wherein R¹ and R² are both alkyl group, as hereindefined.

The term “dialkylaminoalkylcarbonyl” refers to a group—(C═O)-alkyl-NR¹R² wherein R¹ and R² are both alkyl group, as hereindefined.

The term “dihydroxyalkyl” refers to a group alkyl is as herein definedsubstituted by two hydroxyl (—OH) groups.

The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.

The term “heteroaryl” refers to an aryl group as herein defined whereinat least one carbon atom is replaced with a heteroatom. In other words,it refers to 5 to 12 carbon-atom aromatic single rings or ring systemscontaining 2 rings which are fused together, typically containing 5 to 6atoms; in which one or more carbon atoms is replaced by oxygen, nitrogenand/or sulfur atoms where the nitrogen and sulfur heteroatoms mayoptionally be oxidized and the nitrogen heteroatoms may optionally bequaternized. Non-limiting examples of such heteroaryl, include:oxazolyl, thiazolyl, imidazolyl, furanyl and pyrrolyl. Preferably theheteroaryl is a 5- or 6-membered heteroaryl, more preferably the 5- or6-membered heteroaryl is a furyl.

The term “heterocyclyl” refers to non-aromatic, fully saturated orpartially unsaturated cyclic groups (for example, 3 to 7 membermonocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10ring atoms) which have at least one heteroatom in at least one carbonatom-containing ring. Preferably the heterocyclyl is a 5- or 6-memberedheterocyclyl. Each ring of the heterocyclic group containing aheteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogenatoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfurheteroatoms may optionally be oxidized and the nitrogen heteroatoms mayoptionally be quaternized. The heterocyclic group may be attached at anyheteroatom or carbon atom of the ring or ring system, where valenceallows. The rings of multi-ring heterocycles may be fused, bridgedand/or joined through one or more spiro atoms. Non limiting exemplaryheterocyclic groups include aziridinyl, oxiranyl, thiiranyl,piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl,isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl,isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl,pyrrolidinyl, 4H-quinolizinyl, 2-oxopiperazinyl, piperazinyl,homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl,2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl,3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl,tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl,tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl,1-oxido-1-thiomorpholin-4-yl, 1-dioxido-1-thiomorpholin-4-yl,1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl,1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl,and morpholin-4-yl.

The term “heterocyclylalkylaminocarbonyl” refers to a group—(C═O)—NH-alkyl-heterocyclyl, wherein alkyl and heterocyclyl are asherein defined.

The term “(heterocyclyl)(alkyl)aminoalkyl” refers to a group-alkyl-NR¹R² wherein R¹ is an alkyl group and R² is an heterocyclylgroup, wherein alkyl and heterocyclyl are as herein defined.

The term “heterocyclylcarbonyl” refers to a group —(C═O)-heterocyclylwherein heterocyclyl is as herein defined.

The term “heterocyclylalkyl” refers to a group -alkyl-heterocyclylwherein alkyl and heterocyclyl are as herein defined.

The term “heterocyclyloxy” to a group —O-heterocyclyl whereinheterocyclyl is as herein defined.

The term “heterocyclylsulfonyl” refers to a group —SO₂-heterocyclylwherein heterocyclyl is as herein defined.

The term “hydroxyalkyl” refers to a group -alkyl-OH wherein alkyl is asherein defined.

The term “hydroxyalkylaminoalkyl” refers to a group -alkyl-NH-alkyl-OHwherein alkyl is as herein defined.

The term “hydroxycarbonyl” refers to a group —C(═O)—OH wherein carbonylis as herein defined. In other words, “hydroxycarbonyl” corresponds to acarboxylic acid group.

The term “oxo” refers to a ═O substituent.

The term “sulfonylamino” refers to a group —NH—SO₂.

The term “about”, preceding a figure, means plus or less 10% of thevalue of said figure.

The term “administration”, or a variant thereof (e.g. “administering”),means providing the active agent or active ingredient (e.g. a A2Ainhibitor), alone or as part of a pharmaceutically acceptablecomposition, to the patient in whom/which the condition, symptom, ordisease is to be treated or prevented.

The terms “IC₅₀” or “half maximal inhibitory concentration” representthe concentration of an inhibitor that is required for 50% inhibition invitro.

The term “inhibitor” refers to a natural or synthetic compound that hasa biological effect to inhibit or significantly reduce or down-regulatethe expression of a gene and/or a protein or that has a biologicaleffect to inhibit or significantly reduce the biological activity of aprotein. Consequently, an “A2A inhibitor” refers to a compound that hasa biological effect to inhibit or significantly reduce or down-regulatethe biological activity of A2A receptor.

The term “human” refers to a subject of both genders and at any stage ofdevelopment (i.e. neonate, infant, juvenile, adolescent, adult).

The term “patient” refers to a warm-blooded animal, more preferably ahuman, who/which is awaiting the receipt of, or is receiving medicalcare or is/will be the object of a medical procedure.

The expression “pharmaceutically acceptable” refers to the ingredientsof a pharmaceutical composition are compatible with each other and notdeleterious to the subject to which it is administered.

The expression “pharmaceutically acceptable carrier” refers to anexcipient that does not produce an adverse, allergic or other untowardreaction when administered to an animal, preferably a human. It includesany and all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents and the like.For human administration, preparations should meet sterility,pyrogenicity, general safety and purity standards as required byregulatory offices, such as, e.g., FDA Office or EMA.

The term “predrug”, as used herein, means any compound that will bemodified to form a drug species, wherein the modification may take placeeither inside or outside of the body, and either before or after thepredrug reaches the area of the body where administration of the drug isindicated.

The terms “prevent”, “preventing” and “prevention”, as used herein,refer to a method of delaying or precluding the onset of a condition ordisease and/or its attendant symptoms, barring a patient from acquiringa condition or disease, or reducing a patient's risk of acquiring acondition or disease.

The term “prodrug” as used herein means the pharmacologically acceptablederivatives of compounds of Formula I, such as for example esters oramides, whose in vivo biotransformation product generates thebiologically active drug. Prodrugs are generally characterized byincreased bio-availability and are readily metabolized into biologicallyactive compounds in vivo.

The terms “treating” or “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures; wherein the object is toprevent or slow down the targeted pathologic condition or disease. Thosein need of treatment include those already with the disease as well asthose prone to have the disease or those in whom the disease is to beprevented. A subject or mammal is successfully “treated” for a diseaseor affection or condition if, after receiving the treatment according tothe present invention, the subject or mammal shows observable and/ormeasurable reduction in or absence of one or more of the following:reduction of tumors; and/or relief to some extent, for one or more ofthe symptoms associated with the specific disease or condition; reducedmorbidity and mortality, and improvement in quality of life issues. Theabove parameters for assessing successful treatment and improvement inthe disease are readily measurable by routine procedures familiar to aphysician.

The term “volunteer” or “subject” refers to an animal, including ahuman. In the sense of the present invention, a subject may be apatient, i.e., a person receiving medical attention, undergoing orhaving underwent a medical treatment, or monitored for the developmentof a disease. In one embodiment, the subject is a male. In anotherembodiment, the subject is a female.

DETAILED DESCRIPTION

Compounds

This invention relates to compounds of Formula I

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein:    -   R¹ represents 5- or 6-membered heteroaryl or 5- or 6-membered        aryl, wherein heteroaryl or aryl groups are optionally        substituted by one or more substituent selected from C₁-C₆ alkyl        (preferably methyl) and halo (preferably fluoro or chloro);        preferably R¹ represents 5-membered heteroaryl; more preferably        R¹ represents furyl;    -   R² represents 6-membered aryl or 6-membered heteroaryl,        -   wherein heteroaryl or aryl groups are optionally substituted            by one or more substituent selected from halo, alkyl,            heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy,            carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl,            heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl,            aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl,            carbonylamino, sulfonylamino and alkylsulfonealkyl;            -   said substituents being optionally substituted by one or                more substituent selected from oxo, halo, hydroxy,                cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl,                hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl,                aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,                (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl,                heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,                dialkylamino, aminoalkylcarbonylamino,                aminocarbonylalkylamino,                (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,                hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,                aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,                dialkylaminoalkylaminocarbonyl,                heterocyclylalkylaminocarbonyl,                (alkylaminoalkyl)(alkyl)aminocarbonyl,                alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,                heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,                alkylsulfoxide, alkylsulfoxidealkyl alkylsulfonyl and                alkylsulfonealkyl;        -   or the heteroaryl or aryl groups are optionally substituted            with two substituents that form together with the atoms to            which they are attached a 5- or 6-membered aryl ring, a 5-            or 6-membered heretoaryl ring, a 5- or 6-membered cycloalkyl            ring or a 5- or 6-membered heterocyclyl ring; optionally            substituted by one or more substituent selected from oxo,            halo, hydroxy, cyano, alkyl, alkenyl, aldehyde,            heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,            hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl,            dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl,            heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy,            amino, dialkylamino, aminoalkylcarbonylamino,            aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino,            alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl,            aminocarbonyl, aminoalkylaminocarbonyl,            alkylaminoalkylaminocarbonyl,            dialkylaminoalkylaminocarbonyl,            heterocyclylalkylaminocarbonyl,            (alkylaminoalkyl)(alkyl)aminocarbonyl,            alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,            heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,            alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and            alkylsulfonealkyl.

According to one embodiment, in Formula I:

-   -   R¹ represents 5- or 6-membered heteroaryl or 5- or 6-membered        aryl, wherein heteroaryl or aryl groups are optionally        substituted by one or more substituent selected from C₁-C₆ alkyl        (preferably methyl) and halo (preferably fluoro or chloro);        preferably R¹ represents 5-membered heteroaryl; more preferably        R¹ represents furyl;    -   R² represents 6-membered aryl or 6-membered heteroaryl,        -   wherein heteroaryl or aryl groups are optionally substituted            by one or more substituent selected from halo, alkyl,            heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy,            carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl,            heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl,            aminosulfonyl, heterocyclylsulfonyl, carbonylamino,            sulfonylamino and alkylsulfonealkyl;            -   said substituents being optionally substituted by one or                more substituent selected from hydroxy, cyano, alkyl,                alkenyl, aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl,                aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,                (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl,                heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,                dialkylamino, aminoalkylcarbonylamino,                aminocarbonylalkylamino,                (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,                hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,                aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,                dialkylaminoalkylaminocarbonyl,                (alkylaminoalkyl)(alkyl)aminocarbonyl,                alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,                heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,                alkylsulfoxide, alkylsulfoxidealkyl alkylsulfonyl and                alkylsulfonealkyl.

According to one embodiment, in Formula I:

-   -   R¹ represents 5- or 6-membered heteroaryl or 5- or 6-membered        aryl, wherein heteroaryl or aryl groups are optionally        substituted by one or more substituent selected from C₁-C₆ alkyl        (preferably methyl) and halo (preferably fluoro or chloro);        preferably R¹ represents 5-membered heteroaryl; more preferably        R¹ represents furyl;    -   R² represents 6-membered aryl or 6-membered heteroaryl,        -   wherein heteroaryl or aryl groups are optionally substituted            by one or more substituent selected from halo, alkyl,            heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy,            carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl,            heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl,            aminosulfonyl, heterocyclylsulfonyl, carbonylamino and            sulfonylamino;            -   said substituents being optionally substituted by one or                more substituent selected from hydroxy, cyano, alkyl,                alkenyl, aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl,                aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,                (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl,                heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,                dialkylamino, aminoalkylcarbonylamino,                aminocarbonylalkylamino,                (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,                hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,                aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,                dialkylaminoalkylaminocarbonyl,                (alkylaminoalkyl)(alkyl)aminocarbonyl,                alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,                heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,                alkylsulfoxide, alkylsulfoxidealkyl.

According to a preferred embodiment, this invention relates to compoundsof Formula (Ia):

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein:    -   R¹ represents 5- or 6-membered heteroaryl or 5- or 6-membered        aryl, wherein heteroaryl or aryl groups are optionally        substituted by one or more substituent selected from C₁-C₆ alkyl        (preferably methyl) and halo (preferably fluoro or chloro);        preferably R¹ represents 5-membered heteroaryl; more preferably        R¹ represents furyl;    -   X¹ and X² represent each independently C or N;    -   R^(1′) is absent when X¹ is N; or when X¹ is C, R^(1′)        represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy,        heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl,        hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide,        alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl,        alkylsulfonimidoyl, carbonylamino, sulfonylamino or        alkylsulfonealkyl;        -   said substituents being optionally substituted by one or            more substituent selected from oxo, halo, hydroxy, cyano,            alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,            dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,            alkylaminoalkyl, dialkylaminoalkyl,            (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,            alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,            aminoalkylcarbonylamino, aminocarbonylalkylamino,            (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,            hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,            aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,            dialkylaminoalkylaminocarbonyl,            heterocyclylalkylaminocarbonyl,            (alkylaminoalkyl)(alkyl)aminocarbonyl,            alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,            heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,            alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and            alkylsulfonealkyl;    -   R^(2′) represents H, halo, alkyl, heterocyclyl, alkoxy,        cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl,        aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl,        alkylsulfoxide, alkylsulfonyl, aminosulfonyl,        heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino,        sulfonylamino, or alkylsulfonealkyl;        -   said substituents being optionally substituted by one or            more substituent selected from oxo, halo, hydroxy, cyano,            alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,            dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,            alkylaminoalkyl, dialkylaminoalkyl,            (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,            alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,            aminoalkylcarbonylamino, aminocarbonylalkylamino,            (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,            hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,            aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,            dialkylaminoalkylaminocarbonyl,            heterocyclylalkylaminocarbonyl,            (alkylaminoalkyl)(alkyl)aminocarbonyl,            alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,            heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,            alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and            alkylsulfonealkyl;    -   or R^(1′) and R^(2′) form together with the atoms to which they        are attached a 5- or 6-membered aryl ring, a 5- or 6-membered        heretoaryl ring, a 5- or 6-membered cycloalkyl ring or a 5- or        6-membered heterocyclyl ring; optionally substituted by one or        more substituent selected from oxo, halo, hydroxy, cyano, alkyl,        alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,        dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,        hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,        aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,        dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,        alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl;    -   R^(3′) is absent when X² is N; or when X² is C, R^(3′)        represents H or halo, preferably H or F;    -   R^(4′) represents H or halo, preferably H or F; and    -   R^(5′) represents H or halo, preferably H or F.

According to one embodiment, in Formula (Ia):

-   -   R¹ represents 5- or 6-membered heteroaryl or 5- or 6-membered        aryl, wherein heteroaryl or aryl groups are optionally        substituted by one or more substituent selected from C₁-C₆ alkyl        (preferably methyl) and halo (preferably fluoro or chloro);        preferably R¹ represents 5-membered heteroaryl; more preferably        R¹ represents furyl;    -   X¹ and X² represent each independently C or N;    -   R^(1′) is absent when X¹ is N; or when X¹ is C, R^(1′)        represents H, halo, alkyl, alkoxy, heterocyclyloxy,        alkylcarbonyl, carbonyl, aminocarbonyl, hydroxycarbonyl,        heterocyclyl, heterocyclylcarbonyl, alkylsulfoxide,        alkylsulfonyl, aminosulfonyl or heterocyclylsulfonyl;        -   said substituents being optionally substituted by one or            more substituent selected from hydroxy, cyano, alkyl,            hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,            alkylaminoalkyl, dialkylaminoalkyl,            (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,            alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,            aminoalkylcarbonylamino, aminocarbonylalkylamino,            (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl,            alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,            alkylaminoalkylaminocarbonyl,            dialkylaminoalkylaminocarbonyl,            (alkylaminoalkyl)(alkyl)aminocarbonyl,            alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,            heterocyclylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl,            alkylsulfonealkyl;    -   R^(2′) represents H, alkoxy, cycloalkyloxy, heterocyclyloxy,        alkylsulfoxide, carbonyl, carbonylamino, aminocarbonyl or        sulfonylamino;        -   wherein alkoxy, cycloalkyloxy, heterocyclyloxy,            alkylsulfoxide, carbonyl, carbonylamino, aminocarbonyl or            sulfonylamino are optionally substituted by one or more            substituent selected from hydroxy, cyano, alkyl, alkenyl,            aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,            alkylaminoalkyl, dialkylaminoalkyl,            (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,            alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,            aminoalkylcarbonylamino, aminocarbonylalkylamino,            (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino            hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,            aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,            dialkylaminoalkylaminocarbonyl,            (alkylaminoalkyl)(alkyl)aminocarbonyl,            alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,            heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,            alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonealkyl;    -   or R^(1′) and R^(2′) form together with the atoms to which they        are attached a 5- or 6-membered aryl ring, a 5- or 6-membered        heretoaryl ring, a 5- or 6-membered cycloalkyl ring, a 5- or        6-membered heterocyclyl ring; optionally substituted by one or        more substituent selected from hydroxy, cyano, alkyl,        hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl,        alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,        alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylsulfoxide,        alkylsulfonealkyl;    -   R^(3′) is absent when X² is N; or when X² is C, R^(3′)        represents H or halo, preferably H or F;    -   R^(4′) represents H or halo, preferably H or F; and    -   R^(5′) represents H or halo, preferably H or F.

According to one embodiment, in Formula (Ia):

-   -   R¹ represents 5- or 6-membered heteroaryl or 5- or 6-membered        aryl, wherein heteroaryl or aryl groups are optionally        substituted by one or more substituent selected from C₁-C₆ alkyl        (preferably methyl) and halo (preferably fluoro or chloro);        preferably R¹ represents 5-membered heteroaryl; more preferably        R¹ represents furyl;    -   X¹ and X² represent each independently C or N;    -   R^(1′) is absent when X¹ is N; or when X¹ is C, R^(1′)        represents H, halo, alkyl, alkoxy, heterocyclyloxy,        alkylcarbonyl, carbonyl, aminocarbonyl, hydroxycarbonyl,        heterocyclyl, heterocyclylcarbonyl, alkylsulfoxide,        alkylsulfonyl, aminosulfonyl or heterocyclylsulfonyl;        -   said substituents being optionally substituted by one or            more substituent selected from hydroxy, cyano, alkyl,            hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,            alkylaminoalkyl, dialkylaminoalkyl,            (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,            alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,            aminoalkylcarbonylamino, aminocarbonylalkylamino,            (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl,            alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,            alkylaminoalkylaminocarbonyl,            dialkylaminoalkylaminocarbonyl,            (alkylaminoalkyl)(alkyl)aminocarbonyl,            alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,            heterocyclylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl;    -   R^(2′) represents H, alkoxy, cycloalkyloxy, heterocyclyloxy,        alkylsulfoxide, carbonyl, carbonylamino, aminocarbonyl or        sulfonylamino;        -   wherein alkoxy, cycloalkyloxy, heterocyclyloxy,            alkylsulfoxide, carbonyl, carbonylamino, aminocarbonyl or            sulfonylamino are optionally substituted by one or more            substituent selected from hydroxy, cyano, alkyl, alkenyl,            aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,            alkylaminoalkyl, dialkylaminoalkyl,            (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,            alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,            aminoalkylcarbonylamino, aminocarbonylalkylamino,            (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino            hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,            aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,            dialkylaminoalkylaminocarbonyl,            (alkylaminoalkyl)(alkyl)aminocarbonyl,            alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,            heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,            alkylsulfoxide, alkylsulfoxidealkyl;    -   or R^(1′) and R^(2′) form together with the atoms to which they        are attached a 5- or 6-membered aryl ring, a 5- or 6-membered        heretoaryl ring, a 5- or 6-membered cycloalkyl ring, a 5- or        6-membered heterocyclyl ring; optionally substituted by one or        more substituent selected from hydroxy, cyano, alkyl,        hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl,        alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,        alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylsulfoxide;    -   R^(3′) is absent when X² is N; or when X² is C, R^(3′)        represents H or halo, preferably H or F;    -   R^(4′) represents H or halo, preferably H or F; and        -   R^(5′) represents H or halo, preferably H or F.

In one specific embodiment of the invention, R¹ represents 5- or6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl oraryl groups are optionally substituted by one or more substituentselected from C₁-C₆ alkyl (preferably methyl) and halo (preferablyfluoro or chloro).

In a preferred embodiment, R¹ represents 5-membered heteroaryl; morepreferably, R¹ represents furyl.

In one specific embodiment of the invention, X¹ and X² represent eachindependently C or N. In another specific embodiment, X¹ and X² bothrepresent C.

In one specific embodiment of the invention, R^(1′) is absent when X¹ isN.

In another specific embodiment, when X¹ is C, R^(1′) represents H, halo,alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl,alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl,alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl,alkylsulfonimidoyl, carbonylamino, sulfonylamino or alkylsulfonealkyl;said substituents being optionally substituted by one or moresubstituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl,aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

In a preferred embodiment, when X¹ is C, R^(1′) represents H, halo,alkyl, alkoxy, heterocyclyloxy, alkylcarbonyl, carbonyl, aminocarbonyl,hydroxycarbonyl, heterocyclyl heterocyclylcarbonyl, alkylsulfoxide,alkylsulfonyl, aminosulfonyl or heterocyclylsulfonyl; said substituentsbeing optionally substituted by one or more substituent selected fromhydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl,heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl,aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl.

In a preferred embodiment, R^(1′) substituents are optionallysubstituted by one or more substituent selected from halo, hydroxy,alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkylaminoalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino,aminocarbonylalkylamino, heterocyclylalkylaminocarbonyl,(aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl,aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,heterocyclylcarbonyl, alkylsulfoxide and alkylsulfonealkyl.

In a preferred embodiment, R^(1′) substituents are optionallysubstituted by one or more substituent selected from hydroxy, alkyl,hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl,heteroaryl, alkylheteroaryl, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl,aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.

In one specific embodiment of the invention, R^(2′) represents H, halo,alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl,alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl,alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl,alkylsulfonimidoyl, carbonylamino, sulfonylamino, or alkylsulfonealkyl;said substituents being optionally substituted by one or moresubstituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl,aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

In a preferred embodiment, R^(2′) represents H, alkoxy, cycloalkyloxy,heterocyclyloxy, alkylsulfoxide, carbonyl, carbonylamino, aminocarbonylor sulfonylamino; wherein alkoxy, cycloalkyloxy, heterocyclyloxy,alkylsulfoxide, carbonyl, carbonylamino, aminocarbonyl or sulfonylaminoare optionally substituted by one or more substituent selected fromhydroxy, cyano, alkyl, alkenyl, aldehyde, hydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,(alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl,alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl.

In a preferred embodiment, R^(2′) substituents are optionallysubstituted by one or more substituent selected from oxo, halo, hydroxy,cyano, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylaminoalkyl,heteroaryl, alkylheteroaryl, hydroxycarbonyl, alkyloxycarbonyl,aminocarbonyl, heterocyclylalkylaminocarbonyl, alkylaminoalkylcarbonyl,dialkylaminoalkylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.

In a preferred embodiment, R^(2′) substituents are optionallysubstituted by one or more substituent selected from hydroxy, cyano,alkyl, dialkylaminoalkyl, heteroaryl, alkylheteroaryl, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, alkylaminoalkylcarbonyl,dialkylaminoalkylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.

In another specific embodiment of the invention, R^(1′) and R^(2′) formtogether with the atoms to which they are attached a 5- or 6-memberedaryl ring, a 5- or 6-membered heretoaryl ring, a 5- or 6-memberedcycloalkyl ring or a 5- or 6-membered heterocyclyl ring; optionallysubstituted by one or more substituent selected from oxo, halo, hydroxy,cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl,heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

In a preferred embodiment, R^(1′) and R^(2′) form together with theatoms to which they are attached a 5- or 6-membered aryl ring, a 5- or6-membered heretoaryl ring, a 5- or 6-membered cycloalkyl ring, a 5- or6-membered heterocyclyl ring; optionally substituted by one or moresubstituent selected from hydroxy, cyano, alkyl, hydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl,aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.

In one specific embodiment of the invention, R^(3′) is absent when X² isN. In another specific embodiment of the invention, when X² is C, R^(3′)represents H or halo. In a preferred embodiment, when X² is C, R^(3′)represents H or F.

In one specific embodiment of the invention, R^(4′) represents H orhalo. In a preferred embodiment, R^(4′) represents H or F.

In one specific embodiment of the invention, R^(5′) represents H orhalo. In a preferred embodiment, R^(5′) represents H or F.

In one embodiment, preferred compounds of Formula (Ia) are those ofFormula (Ia-1):

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹,R^(1′), R^(2′), R^(3′), R^(4′) and R^(5′) are as defined in Formula(Ia).

In one embodiment, preferred compounds of Formula (Ia-1) are those ofFormula (Ia-1a):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   R¹ and R^(3′) are as defined in Formula (Ia); and    -   R^(1′) represents an alkyl or heterocyclyl group substituted by        one or more group selected from oxo, halo, hydroxy, cyano,        alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,        dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,        hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,        aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,        dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,        alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

According to one embodiment, in Formula (Ia-1a):

-   -   R¹ and R^(3′) are as defined in Formula (Ia); and    -   R^(1′) represents an alkyl or heterocyclyl group substituted by        one or more group selected from hydroxy, cyano, alkyl,        hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl,        alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,        alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylsulfoxide,        alkylsulfonealkyl.

According to one embodiment, in Formula (Ia-1a):

-   -   R¹ and R^(3′) are as defined in Formula (Ia); and    -   R^(1′) represents an alkyl or heterocyclyl group substituted by        one or more group selected from hydroxy, cyano, alkyl,        hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl,        alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,        alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylsulfoxide.

In one specific embodiment of the invention, R^(1″) represents an alkylor heterocyclyl group substituted by one or more group selected fromoxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl,hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl,heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

In a preferred embodiment, R^(1″) represents an alkyl or heterocyclylgroup substituted by one or more group selected from hydroxy, cyano,alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl,heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl,aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkylsulfoxide.

In a preferred embodiment, R^(1″) represents an alkyl or heterocyclylgroup substituted by one or more group selected from hydroxy,heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl,aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.

In one embodiment, preferred compounds of Formula (Ia-1) are those ofFormula (Ia-1b):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   R¹ and R^(3′) are as defined in Formula (Ia);    -   R^(1′) represents H or halo, preferably H or F; and    -   R^(2″) represents an alkyl or heterocyclyl group substituted by        one or more group selected from oxo, halo, hydroxy, cyano,        alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,        dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,        hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,        aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,        dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,        alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

According to one embodiment, in Formula (Ia-1b):

-   -   R¹ and R^(3′) are as defined in Formula (Ia);    -   R^(1′) represents H or halo, preferably H or F; and    -   R^(2″) represents an alkyl or heterocyclyl group substituted by        one or more group selected from hydroxy, cyano, alkyl,        hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl,        alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,        alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylsulfoxide,        alkylsulfonealkyl.

According to one embodiment, in Formula (Ia-1b):

-   -   R¹ and R^(3′) are as defined in Formula (Ia);    -   R^(1′) represents H or halo, preferably H or F; and    -   R^(2″) represents an alkyl or heterocyclyl group substituted by        one or more group selected from hydroxy, cyano, alkyl,        hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl,        alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,        alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylsulfoxide.

In one specific embodiment of the invention, R^(1′) represents H orhalo. In a preferred embodiment, R^(1′) represents H or F.

In one specific embodiment of the invention, R^(2″) represents an alkylor heterocyclyl group substituted by one or more group selected fromoxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl,hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl,heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

In a preferred embodiment, R^(2″) represents an alkyl or heterocyclylgroup substituted by one or more group selected from hydroxy, cyano,alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl,heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl,aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkylsulfoxide.

In a preferred embodiment, R^(2″) represents an alkyl or heterocyclylgroup substituted by one or more group selected from hydroxy, cyano,heteroaryl, alkylheteroaryl, alkyne, hydroxycarbonyl, alkyloxycarbonyl,aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,alkylsulfoxide, alkylsulfonealkyl.

In one embodiment, preferred compounds of Formula (Ia-1) are those ofFormula (Ia-1c) or (Ia-1d):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   R¹ and R^(3′) are as defined in Formula (Ia);    -   R^(1′) represents H or halo, preferably H or F;    -   R^(2′) represents H or halo, preferably H or F;    -   R^(1i) and R^(1ii) represent each independently hydrogen,        hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl,        dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,        hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,        aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,        dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or        alkylsulfonealkyl; and    -   R^(2i) and R^(2ii) represent each independently hydrogen,        hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl,        dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,        hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,        aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,        dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or        alkylsulfonealkyl.

According to one embodiment, in Formula (Ia-1c) or (Ia-1d):

-   -   R¹ and R^(3′) are as defined in Formula (Ia);    -   R^(1′) represents H or halo, preferably H or F;    -   R^(2′) represents H or halo, preferably H or F;    -   R^(1i) and R^(2ii) represent each independently hydrogen,        hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl,        alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,        alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkylsulfoxidealkyl, alkylsulfonealkyl; and    -   R^(2i) and R^(2ii) represent each independently hydrogen,        hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl,        alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,        alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkylsulfoxidealkyl, alkylsulfonealkyl.

According to one embodiment, in Formula (Ia-1c) or (Ia-1d):

-   -   R¹ and R^(3′) are as defined in Formula (Ia);    -   R^(1′) represents H or halo, preferably H or F;    -   R^(2′) represents H or halo, preferably H or F;    -   R^(1i) and R^(2ii) represent each independently hydrogen,        hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl,        alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,        alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkylsulfoxidealkyl, alkylsulfonealkyl; and    -   R^(2i) and R^(2ii) represent each independently hydrogen,        hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl,        alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,        alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkylsulfoxidealkyl, alkylsulfonealkyl.

In one specific embodiment of the invention, R^(1′) represents H orhalo. In a preferred embodiment, R^(1′) represents H or F.

In one specific embodiment of the invention, R^(2′) represents H orhalo. In a preferred embodiment, R^(2′) represents H or F.

In one specific embodiment of the invention, R^(1i) and R^(1ii)represent each independently hydrogen, hydroxy, alkyl, alkenyl,heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkylsulfoxidealkyl or alkylsulfonealkyl.

In a preferred embodiment, R^(1i) and R^(1ii) represent eachindependently hydrogen, hydroxy, alkyl, hydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl,aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkylsulfoxidealkyl, alkylsulfonealkyl.

In a preferred embodiment, R^(1i) and R^(1ii) represent eachindependently hydrogen, alkyl, heterocyclylalkyl, hydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl or heterocyclylalkylaminocarbonyl.

In a preferred embodiment, R^(1i) and R^(1ii) represent eachindependently hydrogen, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or(heterocyclyl)(alkyl)aminoalkyl.

In one specific embodiment of the invention, R^(2i) and R^(2ii)represent each independently hydrogen, hydroxy, alkyl, alkenyl,heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkylsulfoxidealkyl or alkylsulfonealkyl.

In a preferred embodiment, R^(2i) and R^(2ii) represent eachindependently hydrogen, hydroxy, alkyl, hydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl,aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkylsulfoxidealkyl.

In a preferred embodiment, R^(2i) and R^(2ii) represent eachindependently hydrogen, alkyl, heterocyclylalkyl, dihydroxyalkyl,dialkylaminoalkyl or heterocyclylalkylaminocarbonyl. In a preferredembodiment, R^(2i) and R^(2ii) represent each independently hydrogen,alkyl or dialkylaminoalkyl.

In one embodiment, preferred compounds of Formula (Ia) are those ofFormulae (Ia-2) or (Ia-3):

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹,R^(2′), R^(3′), R^(4′) and R^(5′) are as defined in Formula (Ia).

Particularly preferred compounds of Formula I of the invention are thoselisted in Table 1 hereafter.

TABLE 1 Cpd no Structure Chemical name MW  1

3-(2-(4-(4-((1H-1,2,3- triazolo-4yl)methoxy- 2fluorophenyl)piperazine-1-yl)ethyl)-5-amino-(8-(furan- 2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidine-2(3H)-one 577.60  2

5-((4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)methyl)-1,3,4-oxadiazol-2(3H)-one 594.58  3

5-amino-3-(2-(4-(3- fluoropyridin-4- yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one481.51  4

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c] pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetamide 571.56  5

(S)-5-amino-3-(2-(4-(2- fluoro-4-(2-(methyl- sulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 586.66  6

(R)-5-amino-3-(2-(4-(2- fluoro-4-(2-(methyl- sulfinyl)ethoxy)phenyl)-piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 586.66  7

(R,S)-5-amino-3-(2-(4-(2,4- difluoro-5-(2-(methyl-sulfinyl)ethoxy)phenyl) piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one604.65  8a

(+)-5-amino-3-(2-(4-(2,4- difluoro-5-(2-(methyl- sulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 604.65  8b

(−)-5-amino-3-(2-(4-(2,4- difluoro-5-(2-(methyl- sulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 604.65  9

5-amino-8-(furan-2-yl)-3- (2-(4-(4-(2-hydroxyethoxy) phenyl)piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one522.58  10

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)phenoxy)acetic acid 536.56  11

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)phenoxy)acetamide 535.58  12

5-amino-3-(2-(4-(4-(2,3- dihydroxypropoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 552.61  13

5-amino-3-(2-(4-(4-(2- aminoethoxy)phenyl) piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one521.60  14

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl) ethyl)piperazin-1-yl)benzamide 505.55  15

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-methylbenzamide 519.58  16

5-amino-8-(furan-2-yl)-3- (2-(4-(4-(2-morpholino-ethoxy)phenyl)piperazin- 1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 591.68  17

5-amino-3-(2-(4-(4-(2- (dimethylamino)ethoxy)phenyl)piperazin-1-yl)ethyl)- 8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 549.65  18

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)benzenesulfonamide 541.61  19

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c] pyrimidin-3(2H)-yl)ethyl) piperazin-1-yl)-N-methylbenzenesulfonamide 555.63  20

5-amino-8-(furan-2-yl)-3- (2-(4-(4-(methylsulfonyl) phenyl)piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one540.62  21

5-amino-8-(furan-2-yl)-3- (2-(4-(4-(methylsulfinyl) phenyl)piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one524.62  22

3-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)benzamide 505.55  23

5-amino-8-(furan-2-yl)-3- (2-(4-(3-(2-hydroxyethoxy) phenyl)piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one522.58  24

5-amino-3-(2-(4-(2-fluoro- 4-(2-oxo-2-(piperazin-1-yl)ethoxy)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 622.67  25

5-amino-3-(2-(4-(2-fluoro- 4-(piperidin-4-ylmethoxy) phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 593.68  26

5-amino-3-(2-(4-(2-fluoro- 4-(piperazine-1-carbonyl) phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 592.65  27

5-amino-3-(2-(4-(2-fluoro- 4-(2-(piperazin-1-yl)ethoxy)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 608.69  28

5-amino-3-(2-(4-(2-fluoro- 4-(piperazin-1-ylsulfonyl) phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 628.70  29

5-amino-3-(2-(4-(2-fluoro- 4-(methylsulfonyl)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 558.61  30

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-aminoethyl)-3- fluorobenzamide 566.61  31

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2- (methylamino)ethyl) benzamide 580.64  32

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3- fluorobenzamide 594.66  33

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2- hydroxyethyl)benzamide 567.60  34

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-3- fluorobenzamide 597.62  35

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)acetic acid 554.55  36

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3,5- difluorophenoxy) acetic acid 572.54  37

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoic acid 568.58  38

(S)-2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)propanoic acid 568.58  39

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-2- methylpropanoic acid 582.61  40

3-(4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorophenyl)propanoic acid 552.58  41

4-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)butanoic acid 582.61  42

2-(3-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,6-difluorophenoxy) acetic acid 572.54  43

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy) acetic acid 572.54  44

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorobenzoic acid 524.53  45

2-((2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)ethyl) amino)acetamide 596.64 46

2-((2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)ethyl) (methyl)amino)acetamide610.66  47

5-amino-3-(2-(4-(2-fluoro- 4-(piperidin-4-yloxy) phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl) thiazolo[5,4-e][1,2,4] triazolo[1,5-c]pyrimidin-2(3H)-one 579.65  48

5-amino-3-(2-(4-(2-fluoro- 4-(pyrrolidin-3- yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 565.62  49

3-(2-(4-(4-((1H-1,2,4- triazol-3-yl)methoxy)-2-fluorophenyl)piperazin-1- yl)ethyl)-5-amino-8-(furan- 2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 577.59  50

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)-N-(2- (methylamino)ethyl)acetamide 610.66  51

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)-N-(2- (dimethylamino)ethyl)acetamide 624.69  52

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)-N-(2- aminoethyl)acetamide596.64  53

(R)-2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)propanoic acid 568.58  54

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)acetamide 553.57  55

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-methyl-N-(2- (methylamino)ethyl) benzamide 594.66  56

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3- fluoro-N-methylbenzamide 608.69  57

(R)-4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(1- (dimethylamino) propan-2-yl)-3-fluorobenzamide 608.69  58

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)-N-methyl-N-(2-(methylamino)ethyl) acetamide 624.69  59

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4- difluorophenoxy)-2- methylpropanoic acid600.60  60

(S)-2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4- difluorophenoxy) propanoic acid 586.57  61

(R)-2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4- difluorophenoxy) propanoic acid 586.57  62

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2- (methylamino)ethyl) acetamide 628.65  63

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4- difluorophenoxy)-N-(2-(dimethylamino)ethyl) acetamide 642.68  64

5-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)- 2,4-difluoro-N- methylbenzamide 626.69  65

4-(5-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4- difluorophenoxy) butanoic acid 600.60  66

3-(2-(4-(5-((1H-tetrazol-5- yl)methoxy)-2,4- difluorophenyl)piperazin-1-yl)ethyl)-5-amino-8-(furan- 2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 596.58  67

5-amino-3-(2-(4-(2-fluoro- 4-((1-methyl-1H-1,2,4- triazol-3-yl)methoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 591.62  68

5-amino-3-(2-(4-(2,4- difluoro-5-((1-methyl-1H- 1,2,4-triazol-3-yl)methoxy)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 609.62  69

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl) ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methyl (oxetan-3-yl)amino)ethyl) benzamide 636.70  70

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-((2- hydroxyethyl)amino)ethyl) benzamide 610.67  71

2-amino-N-(2-(4-(4-(2-(5- amino-8-(furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c] pyrimidin-3(2H)-yl) ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl) acetamide 596.64  72

(S)-2-amino-N-(2-(4-(4-(2- (5-amino-8-(furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)-3- methylbutanamide 638.72  73

ethyl 2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c] pyrimidin-3(2H)-yl) ethyl)piperazin-1-yl)-2,4-difluorophenoxy) acetate 600.60  74

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy) acetonitrile 553.54  75

5-amino-8-(furan-2-yl)-3- (2-(4-(pyridin-4-yl) piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one463.52  76

5-amino-8-(furan-2-yl)-3- (2-(4-(pyrimidin-4- yl)piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one464.50  77

5-amino-3-(2-(4-(2,4- difluoro-5-(2-(methyl- sulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 620.65  78

5-amino-3-(2-(4-(2-fluoro- 4-(2-(methyl- sulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 602.66  79

5-amino-3-(2-(4-(6-fluoro- 2-oxoindolin-5- yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one535.55  80

5-amino-3-(2-(4-(2-fluoro- 4-(S- methylsulfonimidoyl)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][l,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 557.62  81

5-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)- 2,4-difluorobenzamide 612.65  82

5-amino-3-(2-(4-(5-fluoro- 2-methylpyridin-4-yl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 495.53  83

5-amino-3-(2-(4-(2-fluoro- 4-(((3R,4R)-4- hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 582.61  84

5-amino-3-(2-(4-(2-fluoro- 4-(((3S,4S)-4- hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 582.61  85

5-amino-3-(2-(4-(2-fluoro- 4-(2-hydroxy-2-methyl-propoxy)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 568.62  86

5-amino-3-(2-(4-(2-fluoro- 4-(2-hydroxypropan-2- yl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 538.60  87

5-amino-3-(2-(4-(2-fluoro- 4-(3,3,3-trifluoro-2- hydroxypropoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 608.57  88

5-amino-3-(2-(4-(2-fluoro- 5-(2-hydroxy- ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 540.57  89

5-amino-3-(2-(4-(2,4- difluoro-5-(morpholin-2-ylmethoxy)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 613.64  90

5-amino-3-(2-(4-(2,4- difluoro-5-(morpholin-3- ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 613.64  91

5-amino-3-(2-(4-(2,4- difluoro-5-(((3S,4S)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 601.60  92

5-amino-3-(2-(4-(2,4- difluoro-5-(((3S,4S)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 601.60  93

5-amino-3-(2-(4-(2,4- difluoro-5-(((3R,4S)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 601.60  94

5-amino-3-(2-(4-(2,4- difluoro-5-(((3S,4R)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 601.60  95

(S)-5-amino-3-(2-(4-(2,4- difluoro-5-((2- oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 597.60  96

(R)-5-amino-3-(2-(4-(2,4- difluoro-5-((2- oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 597.60  97

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2- morpholinoethyl)acetamide 684.72  98

5-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(morpholin-3- ylmethyl)benzamide 640.66  99

5-amino-3-(2-(4-(2-fluoro- 4-(morpholin-3- ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 595.65 100

5-amino-3-(2-(4-(2-fluoro- 4-(morpholin-2- ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 595.65 101

5-amino-3-(2-(4-(2-fluoro- 4-(((3R,4R)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 583.61 102

5-amino-3-(2-(4-(2-fluoro- 4-(((3S,4S)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 583.61 103

5-amino-3-(2-(4-(2-fluoro- 4-(((3R,4S)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c1pyrimidin-2(3H)-one 583.61 104

5-amino-3-(2-(4-(2-fluoro- 4-(((3S,4R)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 583.61 105

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2- morpholinoethyl)acetamide 666.73 106

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2- morpholinoethyl)benzamide 636.70 107

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(morpholin-3- ylmethyl)benzamide 622.67 108

5-amino-3-(2-(4-(4- (azetidin-3- yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 533.61 109

(S)-5-amino-3-(2-(4-(2,4- difluoro-5-(methyl- sulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 560.60 110

(R)-5-amino-3-(2-(4-(2,4- difluoro-5-(methyl- sulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 560.60 111

5-amino-3-(2-(4-(2,4- difluoro-5-(((1s,4s)-1- oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 630.69 112

5-amino-3-(2-(4-(2,4- difluoro-5-(((1r,4r)-1- oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 630.69 113

(S)-5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2- (methylsulfinyl)ethyl) benzamide 631.68 114

(R)-5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2- (methylsulfinyl)ethyl) benzamide 631.68 115

(S)-5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2- (methylsulfinyl)ethyl) benzamide 645.70 116

(R)-5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2- (methylsulfinyl)ethyl) benzamide 645.70 117

5-amino-3-(2-(4-(2,4- difluoro-5-(1- oxidothiomorpholine-4-carbonyl)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 643.69 118

5-amino-3-(2-(4-(2,4- difluoro-5-(1-oxidothio- morpholino)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 615.68 119

(R)-5-amino-3-(2-(4-(2- fluoro-4-(methyl- sulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 542.61 120

(S)-5-amino-3-(2-(4-(2- fluoro-4-(methyl- sulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 542.61 121

5-amino-3-(2-(4-(2-fluoro- 4-(((1s,4s)-1- oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 612.70 122

5-amino-3-(2-(4-(2-fluoro- 4-(((1r,4r)-1- oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 612.70 123

(S)-4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methyl- sulfinyl)ethyl)benzamide 613.69 124

(R)-4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methyl- sulfinyl)ethyl)benzamide 613.69 125

5-amino-3-(2-(4-(2-fluoro- 4-(1-oxidothiomorpholine- 4-carbonyl)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 625.70 126

5-amino-3-(2-(4-(2-fluoro- 4-(1-oxidothio- morpholino)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 597.69 127

(S)-5-amino-3-(2-(4-(5-(2,3- dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 588.59 128

(R)-5-amino-3-(2-(4-(5- (2,3-dihydroxypropoxy)- 2,4-difluorophenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 588.59 129

(S)-5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4- difluorobenzamide 615.61 130

(R)-5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4- difluorobenzamide 615.61 131

5-amino-3-(2-(4-(4- (azetidin-3-yloxy)-2- fluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 551.60 132

5-amino-3-(2-(4-(5- (azetidin-3-yloxy)-2,4- difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 569.59 133

(S)-5-amino-3-(2-(4-(2,4- difluoro-5-(3-(methyl-sulfinyl)propoxy)phenyl) piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one618.68and pharmaceutically acceptable salts and solvates thereof.

In Table 1, the term “Cpd” means compound.

The compounds of Table 1 were named using ChemBioDraw® Ultra version12.0 (PerkinElmer).

All references to compounds of Formula I and subformulae thereof includereferences to enantiomers, salts, solvates, polymorphs, multi-componentcomplexes and liquid crystals thereof.

The compounds of the invention include compounds of Formula I andsubformulae thereof as hereinbefore defined, including all polymorphsand crystal habits thereof, prodrugs and isomers thereof (includingoptical, geometric and tautomeric isomers) and isotopically-labeledcompounds of Formula I and subformulae thereof.

The compounds of Formula I and subformulae thereof may contain anasymmetric center and thus may exist as different stereoisomeric forms.Accordingly, the present invention includes all possible stereoisomersand includes not only racemic compounds but the individual enantiomersand their non-racemic mixtures as well. When a compound is desired as asingle enantiomer, such may be obtained by stereospecific synthesis, byresolution of the final product or any convenient intermediate, or bychiral chromatographic methods as each are known in the art. Resolutionof the final product, an intermediate, or a starting material may beperformed by any suitable method known in the art.

The compounds of the invention may be in the form of pharmaceuticallyacceptable salts. Pharmaceutically acceptable salts of the compounds ofFormula I and subformulae thereof include the acid addition and basesalts thereof. Suitable acid addition salts are formed from acids whichform non-toxic salts. Examples include the acetate, adipate, aspartate,benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate,camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate,gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,isethionate, lactate, malate, maleate, malonate, mesylate,methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate,tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable basesalts are formed from bases which form non-toxic salts. Examples includethe aluminium, arginine, benzathine, calcium, choline, diethylamine,diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium,sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine,4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids andbases may also be formed, for example, hemisulphate and hemicalciumsalts. Preferred, pharmaceutically acceptable salts includehydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate,nitrate, citrate, and acetate.

When the compounds of the invention contain an acidic group as well as abasic group the compounds of the invention may also form internal salts,and such compounds are within the scope of the invention. When thecompounds of the invention contain a hydrogen-donating heteroatom (e.g.NH), the invention also covers salts and/or isomers formed by transferof said hydrogen atom to a basic group or atom within the molecule.

Pharmaceutically acceptable salts of compounds of Formula I andsubformulae thereof may be prepared by one or more of these methods:

-   -   (i) by reacting the compound of Formula I with the desired acid;    -   (ii) by reacting the compound of Formula I with the desired        base;    -   (iii) by removing an acid- or base-labile protecting group from        a suitable precursor of the compound of Formula I or by        ring-opening a suitable cyclic precursor, for example, a lactone        or lactam, using the desired acid; or    -   (iv) by converting one salt of the compound of Formula I to        another by reaction with an appropriate acid or by means of a        suitable ion exchange column.

All these reactions are typically carried out in solution. The salt, mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionization in thesalt may vary from completely ionized to almost non-ionized.

The compounds of the present invention may be administered in the formof pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” is intended to include all acceptable salts such asacetate, lactobionate, benzenesulfonate, laurate, benzoate, malate,bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate,borate, methylbromide, bromide, methylnitrate, calcium edetate,methylsulfate, camsylate, mucate, carbonate, napsylate, chloride,nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt,dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate(embonate), estolate, palmitate, esylate, pantothenate, fumarate,phosphate/diphosphate, gluceptate, polygalacturonate, gluconate,salicylate, glutamate, stearate, glycollylarsanilate, sulfate,hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide,tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide,tosylate, isothionate, triethiodide, lactate, panoate, valerate, and thelike which can be used as a dosage form for modifying the solubility orhydrolysis characteristics or can be used in sustained release orpro-drug formulations. Depending on the particular functionality of thecompound of the present invention, pharmaceutically acceptable salts ofthe compounds of this invention include those formed from cations suchas sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, andfrom bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylene-diamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine,diethylamine, piperazine, tris(hydroxymethyl)aminomethane, andtetramethylammonium hydroxide.

These salts may be prepared by standard procedures, e.g. by reacting afree acid with a suitable organic or inorganic base. Where a basic groupis present, such as amino, an acidic salt, i.e. hydrochloride,hydrobromide, acetate, palmoate, and the like, can be used as the dosageform.

In addition, although generally, with respect to the salts of thecompounds of the invention, pharmaceutically acceptable salts arepreferred, it should be noted that the invention in its broadest sensealso included non-pharmaceutically acceptable salts, which may forexample be used in the isolation and/or purification of the compounds ofthe invention. For example, salts formed with optically active acids orbases may be used to form diastereoisomeric salts that can facilitatethe separation of optically active isomers of the compounds of Formula Iabove.

The compounds of the invention may be in the form of pharmaceuticallyacceptable solvates. Pharmaceutically acceptable solvates of thecompounds of Formula I and subformulae thereof contains stoichiometricor sub-stoichiometric amounts of one or more pharmaceutically acceptablesolvent molecule such as ethanol or water. The term “hydrate” refers towhen the said solvent is water.

The invention also generally covers all pharmaceutically acceptablepredrugs and prodrugs of the compounds of Formula I and subformulaethereof.

Also, in the case of an alcohol group being present, pharmaceuticallyacceptable esters can be employed, e.g. acetate, maleate,pivaloyloxymethyl, and the like, and those esters known in the art formodifying solubility or hydrolysis characteristics for use as sustainedrelease or prodrug formulations.

Process for Manufacturing

The compounds of Formula I can be prepared by different ways withreactions known to a person skilled in the art.

The invention further relates to a process for manufacturing ofcompounds of Formula (Ia):

-   -   and pharmaceutically acceptable salts and solvates thereof,        wherein X¹, X², R¹, R^(1′), R^(2′), R^(3′), R^(4′) and R^(5′)        are as defined in Formula (Ia);    -   comprising:    -   (a1) reacting a compound of Formula (A)

-   -   -   wherein X¹, X², R^(1′), R^(2′), R^(3′), R^(4′) and R^(5′)            are as defined in Formula (Ia);

    -   with a compound of Formula (B)

-   -   -   wherein R¹ is as defined in Formula (Ia);            -   Y represents an halogen (preferably iodine, bromine or                chlorine), an alkylsulfonyloxy having 1-6 carbon atoms                (preferably methylsulfonyloxy or                trifluoromethylsulfonyloxy) or arylsulfonyloxy having                6-10 carbon atoms (preferably phenyl- or                p-tolylsulfonyloxy), or any leaving group known to those                skilled in the art.

According to one embodiment, step (a1) of the process of the inventionmay be performed in the presence or absence of bases. In a specificembodiment, step (a1) of the process of the invention is performed inthe presence of bases selected from the group consisting of but notlimited to TEA, DIPEA, Pyridine, NaOH, K₃PO₄, K₂CO₃, Na₂CO₃, preferablyDIPEA or TEA.

According to one embodiment, step (a1) of the process of the inventionmay be performed in the presence of a suitable solvent such as but notlimited to DMF, dioxane, THF, water or mixtures thereof, preferably inDMF.

According to one embodiment, step (a1) of the process of the inventionmay be performed at a temperature ranging from 20° C. to about 180° C.,with or without microwave irradiation, for a period ranging from 10minutes to a few hours, e.g. 10 minutes to 24 h.

Compounds of Formula (B) can be prepared according to the followingScheme:

Step (b1): 5-Aminothiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione can beconverted to5-amino-7-hydroxy-3-(2-methoxyethyl)-2H,3H-[1,3]thiazolo[4,5-d]pyrimidin-2-one.

According to one embodiment, step (b1) can be performed by treatmentwith 1-bromo-2-methyoxy ethane, 1-iodo-2-methoxy ethane,1-mesyl-2-methoxy ethane or 1-tosyl-2-methoxy ethane, preferably1-bromo-2-methyoxy ethane.

According to one embodiment, step (b1) of the process of the inventionmay be performed in the presence or absence of bases. In a specificembodiment, step (b1) is performed in the presence of bases such as butnot limited to sodium tert-butoxide, potassium tert-butoxide, NaH, CsOH,NaOH, K₂CO₃, Na₂CO₃, preferably sodium tert-butoxide, potassiumtert-butoxide or NaH.

According to one embodiment, step (b1) of the process of the inventionmay be performed in the presence of a suitable solvent such as but notlimited to DMF, dioxane, THF, DMA, preferably in DMF.

According to one embodiment, step (b1) of the process of the inventionmay be performed at a temperature ranging from 20° C. to about 180° C.,with or without microwave irradiation, for a period ranging from 10minutes to a few hours, e.g. 10 minutes to 24 h.

Step (b2):5-amino-7-hydroxy-3-(2-methoxyethyl)-2H,3H-[1,3]thiazolo[4,5-d]pyrimidin-2-onecan be converted to5-amino-7-chloro-3-(2-methoxyethyl)-2H,3H-[1,3]thiazolo[4,5-d]pyrimidin-2-one.

According to one embodiment, step (b2) may be performed in presence of achlorinating agent, such as but not limited to POCl₃, PCl₅, SOCl₂,preferably POCl₃.

According to one embodiment, step (b2) of the process of the inventionmay be performed in the presence or absence of a suitable solvent,preferably in absence of solvents.

According to one embodiment, step (b2) of the process of the inventionmay be performed at a temperature ranging from 20° C. to about 180° C.,with or without microwave irradiation, for a period ranging from 10minutes to a few hours, e.g. 10 minutes to 24 h.

Step (b3):5-amino-7-chloro-3-(2-methoxyethyl)-2H,3H-[1,3]thiazolo[4,5-d]pyrimidin-2-onecan be converted to a compound of Formula (D), wherein R¹ is as definedin Formula (Ia), by reacting with a compound of Formula (C), wherein R¹is as defined in Formula (Ia).

According to one embodiment, step (b3) of the process of the inventionmay be performed in the presence of a suitable base.

According to one embodiment, step (b3) of the process of the inventionmay be performed in the presence or absence of a suitable solvent suchas ethanol, propanol, methanol, THF, water, dioxane, or mixturesthereof, preferably in presence of ethanol.

According to one embodiment, step (b3) of the process of the inventionmay be performed at a temperature ranging from 20° C. to about 180° C.,with or without microwave irradiation, for a period ranging from 10minutes to a few hours, e.g. 10 minutes to 24 h.

Step (b4): Compound of Formula (D), wherein R¹ is as defined in Formula(Ia), can be converted to a compound of Formula (E), wherein R¹ is asdefined in Formula (Ia).

According to one embodiment, step (b4) of the process of the inventionmay be performed in the presence of N,O-Bis(trimethylsilyl)acetamide.

According to one embodiment, step (b4) of the process of the inventionmay be performed in the presence or absence of hexamethyldisilazane.

According to one embodiment, step (b4) of the process of the inventionmay be performed in the presence or absence of a suitable solvent,preferably in the absence of solvent.

According to one embodiment, step (b4) of the process of the inventionmay be performed at a temperature ranging from 20° C. to about 180° C.,with or without microwave irradiation, for a period ranging from 1 hourto a few hours, e.g. 1 h to 96 h.

Step (b5): Compound of Formula (E), wherein R¹ is as defined in Formula(Ia), can be converted to a compound of Formula (F), wherein R¹ is asdefined in Formula (Ia).

According to one embodiment, step (b5) of the process of the inventionmay be performed in the presence of BBr₃.

According to one embodiment, step (b5) of the process of the inventionmay be performed in the presence or absence of a suitable solvent suchas DCM, THF, preferably in the presence of DCM.

According to one embodiment, step (b5) of the process of the inventionmay be performed at a temperature ranging from −20° C. to about 50° C.,with or without microwave irradiation, for a period ranging from 10minutes to a few hours, e.g. 10 minutes to 24 h.

Step (b6): Compound of Formula (F), wherein R¹ is as defined in Formula(Ia), can be converted to a compound of Formula (B), wherein R¹ and Yare as defined in Formula (Ia).

According to one embodiment, step (b6) of the process of the inventionmay be performed using any reagent known to those skilled in the art forthe conversion of an alcohol to an alkyl halide, or to an alkyl or arylsulfonic ester, depending on the nature of Y, such as but not limited totosyl chloride, mesyl chloride, triflic chloride, triflic anhydride,SOCl₂, SO₂Cl₂, POCl₃, PCl₅, preferably tosyl chloride or mesyl chloride.

According to one embodiment, step (b6) of the process of the inventionmay be performed in the presence of a suitable base, such as but notlimited to TEA or DIPEA.

According to one embodiment, step (b6) of the process of the inventionmay be performed in the presence or absence of a suitable solvent suchas DMF, DCM, THF, preferably in the presence of DMF.

According to one embodiment, step (b6) of the process of the inventionmay be performed at a temperature ranging from −20° C. to about 50° C.,with or without microwave irradiation, for a period ranging from 10minutes to a few hours, e.g. 10 minutes to 24 h.

In general, the synthesis pathways for any individual compound ofFormula (I) will depend on the specific substituents of each moleculeand upon the ready availability of intermediates necessary; again suchfactors being appreciated by those of ordinary skill in the art.

According to a further general process, compounds of Formula I can beconverted to alternative compounds of Formula I, employing suitableinterconversion techniques well known by a person skilled in the art.

Compounds of the Formula I and related formulae can furthermore beobtained by liberating compounds of the Formula I from one of theirfunctional derivatives by treatment with a solvolysing orhydrogenolysing agent.

Preferred starting materials for the solvolysis or hydrogenolysis arethose which conform to the Formula I and related formulae, but containcorresponding protected amino and/or hydroxyl groups instead of one ormore free amino and/or hydroxyl groups, preferably those which carry anamino-protecting group instead of an H atom bonded to an N atom, inparticular those which carry an R*—N group, in which R* denotes anamino-protecting group, instead of an HN group, and/or those which carrya hydroxyl-protecting group instead of the H atom of a hydroxyl group,for example those which conform to the Formula I, but carry a —COOR**group, in which R** denotes a hydroxyl-protecting group, instead of a—COOH group.

It is also possible for a plurality of—identical or different—protectedamino and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, they can in many cases be cleaved off selectively.

The term “amino-protecting group” is known in general terms and relatesto groups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but which are easy to remove after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are, in particular, unsubstituted orsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since theamino-protecting groups are removed after the desired reaction (orreaction sequence), their type and size are furthermore not crucial;however, preference is given to those having 1-20, in particular 1-8,carbon atoms. The term “acyl group” is to be understood in the broadestsense in connection with the present process. It includes acyl groupsderived from aliphatic, araliphatic, aromatic or heterocyclic carboxylicacids or sulfonic acids, and, in particular, alkoxy-carbonyl,aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of suchacyl groups are alkanoyl, such as acetyl, propionyl and butyryl;aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl;aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxy-carbonyl,ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl)and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ(“carbobenzoxy”), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl,such as Mtr. Preferred amino-protecting groups are BOC and Mtr,further¬more CBZ, Fmoc, benzyl and acetyl.

The term “hydroxyl-protecting group” is likewise known in general termsand relates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but are easy to remove after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are the above-mentioned unsubstituted orsubstituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.The nature and size of the hydroxyl-protecting groups are not crucialsince they are removed again after the desired chemical reaction orreaction sequence; preference is given to groups having 1-20, inparticular 1-10, carbon atoms. Examples of hydroxyl-protecting groupsare, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl,p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butylare particularly preferred.

The compounds of the Formula I and related formulae are liberated fromtheir functional derivatives—depending on the protecting group used—forexample strong inorganic acids, such as hydrochloric acid, perchloricacid or sulfuric acid, strong organic carboxylic acids, such astrichloroacetic acid, TFA or sulfonic acids, such as benzene- orp-toluenesulfonic acid. The presence of an additional inert solvent ispossible, but is not always necessary. Suitable inert solvents arepreferably organic, for example carboxylic acids, such as acetic acid,ethers, such as tetrahydrofuran or dioxane, amides, such as DMF,halogenated hydrocarbons, such as dichloromethane, furthermore alsoalcohols, such as methanol, ethanol or isopropanol, and water. Mixturesof the above-mentioned solvents are furthermore suitable. TFA ispreferably used in excess without addition of a further solvent, andperchloric acid is preferably used in the form of a mixture of aceticacid and 70% perchloric acid in the ratio 9:1. The reaction temperaturesfor the cleavage are advantageously between about 0 and about 50° C.,preferably between 15 and 30° C. (room temperature).

The BOC, OtBu and Mtr groups can, for example, preferably be cleaved offusing TFA in dichloromethane or using approximately 3 to 5N HCl indioxane at 15-30° C., and the FMOC group can be cleaved off using anapproximately 5 to 50% solution of dimethylamine, diethylamine orpiperidine in DMF at 15-30° C.

Protecting groups which can be removed hydrogenolytically (for exampleCBZ, benzyl or the liberation of the amidino group from the oxadiazolederivative thereof) can be cleaved off, for example, by treatment withhydrogen in the presence of a catalyst (for example a noble-metalcatalyst, such as palladium, advantageously on a support, such ascarbon). Suitable solvents here are those indicated above, inparticular, for example, alcohols, such as methanol or ethanol, oramides, such as DMF. The hydrogenolysis is generally carried out attemperatures between about 0 and 100° C. and pressures between about 1and 200 bar, preferably at 20-30° C. and 1-10 bar. Hydrogenolysis of theCBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol orusing ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at20-30° C.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide, N-methylpyrrolidone (NMP) or dimethyl-formamide(DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formicacid or acetic acid; nitro compounds, such as nitromethane ornitrobenzene; esters, such as ethyl acetate, or mixtures of the saidsolvents.

Esters can be hydrolyzed, for example, using HCl, H₂SO₄, or using LiOH,NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, attemperatures between 0 and 100° C.

Free amino groups can furthermore be acylated in a conventional mannerusing an acyl chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide, advantageously in an inert solvent, such asdichloromethane or THF and/or in the presence of a base, such astriethylamine or pyridine, at temperatures between −60° C. and +30° C.

For all the protection and deprotection methods, see Philip J.Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart, NewYork, 1994 and, Theodora W. Greene and Peter G. M. Wuts in “ProtectiveGroups in Organic Synthesis”, Wiley Interscience, 3rd Edition 1999.

Reaction schemes as described in the example section are illustrativeonly and should not be construed as limiting the invention in any way.

Intermediates of Synthesis

The invention also relates to intermediates of synthesis of Formula (A)

-   -   and salts and solvates thereof, wherein:    -   R^(1′) is absent when X¹ is N; or when X¹ is C, R^(1′)        represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy,        heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl,        hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide,        alkylsulfonyl, aminosulfonyl heterocyclylsulfonyl        alkylsulfonimidoyl, carbonylamino, sulfonylamino or        alkylsulfonealkyl;        -   said substituents being optionally substituted by one or            more substituent selected from oxo, halo, hydroxy, cyano,            alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,            dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,            alkylaminoalkyl, dialkylaminoalkyl,            (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,            alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,            aminoalkylcarbonylamino, aminocarbonylalkylamino,            (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,            hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,            aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,            dialkylaminoalkylaminocarbonyl,            heterocyclylalkylaminocarbonyl,            (alkylaminoalkyl)(alkyl)aminocarbonyl,            alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,            heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,            alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and            alkylsulfonealkyl;    -   R^(2′) represents H, halo, alkyl, heterocyclyl, alkoxy,        cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl,        aminocarbonyl arbonyl, heterocyclylcarbonyl, alkylsulfoxide,        alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl,        alkylsulfonimidoyl, carbonylamino, sulfonylamino or        alkylsulfonealkyl;        -   said substituents being optionally substituted by one or            more substituent selected from oxo, halo, hydroxy, cyano,            alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,            dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,            alkylaminoalkyl, dialkylaminoalkyl,            (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,            alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,            aminoalkylcarbonylamino, aminocarbonylalkylamino,            (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,            hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,            aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,            dialkylaminoalkylaminocarbonyl,            heterocyclylalkylaminocarbonyl,            (alkylaminoalkyl)(alkyl)aminocarbonyl,            alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,            heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,            alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and            alkylsulfonealkyl;    -   or R^(1′) and R^(2′) form together with the atoms to which they        are attached a 5- or 6-membered aryl ring, a 5- or 6-membered        heretoaryl ring, a 5- or 6-membered cycloalkyl ring or a 5- or        6-membered heterocyclyl ring; optionally substituted by one or        more substituent selected from oxo, halo, hydroxy, cyano, alkyl,        alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,        dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,        hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,        aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,        dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,        alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl;    -   R^(3′) is absent when X² is N; or when X² is C, R^(3′)        represents H or halo, preferably H or F;    -   R^(4′) represents H or halo, preferably H or F; and    -   R^(5′) represents H or halo, preferably H or F.

According to one embodiment, the intermediates of synthesis of Formula(A) used in the process of the invention are selected from the groupconsisting of:

-   1-(4-((1H-1,2,3-triazol-5-yl)methoxy)-2-fluorophenyl)piperazine;-   1-(2-fluoro-4-(prop-2-yn-1-yloxy)phenyl)piperazine;-   2-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)acetamide;-   (S)-1-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazine;-   (R)-1-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazine;-   (R,S)-1-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine;-   (S)-1-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine;    and-   (R)-1-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine.

Uses

The invention is further directed to the use of the compounds of theinvention or pharmaceutically acceptable salts and solvates thereof asA2A inhibitors.

Accordingly, in a particularly preferred embodiment, the inventionrelates to the use of compounds of Formula I and subformulae inparticular those of Table 1 above, or pharmaceutically acceptable saltsand solvates thereof, as A2A inhibitors.

Accordingly, in another aspect, the invention relates to the use ofthese compounds or salts and solvates thereof for the synthesis ofpharmaceutical active ingredients, such as A2A inhibitors.

According to a further feature of the present invention there isprovided a method for modulating A2A activity, in a patient, preferablya warm-blooded animal, and even more preferably a human, in need of suchtreatment, which comprises administering to said patient an effectiveamount of compound of the present invention, or a pharmaceuticallyacceptable salt and solvate thereof.

In one embodiment, the invention relates to the use of compounds ofFormula I and subformulae in particular those of Table 1 above, orpharmaceutically acceptable salts and solvates thereof, for increasingimmune recognition and destruction of the cancer cells.

The compounds of the invention are therefore useful as medicaments, inparticular for the prevention and/or treatment of cancer.

The invention further relates to a method for treatment or prevention ofcancer, which comprises administering to a mammalian species in needthereof a therapeutically effective amount of the compound according tothe invention or a pharmaceutically acceptable salt or solvate thereof.

The invention further provides the use of a compound of Formula I or apharmaceutically acceptable salt and solvate thereof for the manufactureof a medicament for treating and/or preventing cancer.

The invention also provides for a method for delaying in patient theonset of cancer comprising the administration of a pharmaceuticallyeffective amount of a compound of Formula I or pharmaceuticallyacceptable salt and solvate thereof to a patient in need thereof.

Preferably, the patient is a warm-blooded animal, more preferably ahuman.

Various cancers are known in the art. The cancer may be metastatic ornon-metastatic. The cancer may be may be familial or sporadic. In someembodiments, the cancer is selected from the group consisting of:leukemia and multiple myeloma. Additional cancers that can be treatedusing the methods of the invention include, for example, benign andmalignant solid tumors and benign and malignant non-solid tumors. In aspecific embodiment, the cancer is selected from breast, carcinoid,cervical, colorectal, endometrial, glioma, head and neck, liver, lung,melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid andurothelial cancers. In a specific embodiment, the cancer is breastcancer. In a specific embodiment, the cancer is carcinoid cancer. In aspecific embodiment, the cancer is cervical cancer. In a specificembodiment, the cancer is colorectal cancer. In a specific embodiment,the cancer is endometrial cancer. In a specific embodiment, the canceris glioma. In a specific embodiment, the cancer is head and neck cancer.In a specific embodiment, the cancer is liver cancer. In a specificembodiment, the cancer is lung cancer. In a specific embodiment, thecancer is melanoma. In a specific embodiment, the cancer is ovariancancer. In a specific embodiment, the cancer is pancreatic cancer. In aspecific embodiment, the cancer is prostate cancer. In a specificembodiment, the cancer is renal cancer. In a specific embodiment, thecancer is gastric cancer. In a specific embodiment, the cancer isthyroid cancer. In a specific embodiment, the cancer is urothelialcancer.

Examples of solid tumors include, but are not limited to: biliary tractcancer, brain cancer (including glioblastomas and medulloblastomas),breast cancer, carcinoid, cervical cancer, choriocarcinoma, coloncancer, colorectal cancer, endometrial cancer, esophageal cancer,gastric cancer, glioma, head and neck cancer, intraepithelial neoplasms(including Bowen's disease and Paget's disease), liver cancer, lungcancer, neuroblastomas, oral cancer (including squamous cell carcinoma),ovarian cancer (including those arising from epithelial cells, stromalcells, germ cells and mesenchymal cells), pancreatic cancer, prostatecancer, rectal cancer, renal cancer (including adenocarcinoma and Wilmstumor), sarcomas (including leiomyosarcoma, rhabdomyosarcoma,liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (includingmelanoma, Kaposi's sarcoma, basocellular cancer and squamous cellcancer), testicular cancer including germinal tumors (seminomas, andnon-seminomas such as teratomas and choriocarcinomas), stromal tumors,germ cell tumors, thyroid cancer (including thyroid adenocarcinoma andmedullary carcinoma) and urothelial cancer.

Examples of solid tumors include, but are not limited to: biliary tractcancer, brain cancer (including glioblastomas and medulloblastomas),breast cancer, cervical cancer, choriocarcinoma, colon cancer,endometrial cancer, esophageal cancer, gastric cancer, intraepithelialneoplasms (including Bowen's disease and Paget's disease), liver cancer,lung cancer, neuroblastomas, oral cancer (including squamous cellcarcinoma), ovarian cancer (including those arising from epithelialcells, stromal cells, germ cells and mesenchymal cells), pancreaticcancer, prostate cancer, rectal cancer, renal cancer (includingadenocarcinoma and Wilms tumor), sarcomas (including leiomyosarcoma,rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skincancer (including melanoma, Kaposi's sarcoma, basocellular cancer andsquamous cell cancer), testicular cancer including germinal tumors(seminomas, and non-seminomas such as teratomas and choriocarcinomas),stromal tumors, germ cell tumors, and thyroid cancer (including thyroidadenocarcinoma and medullary carcinoma).

Examples of non-solid tumors include but are not limited tohematological neoplasms. As used herein, a hematologic neoplasm is aterm of art which includes lymphoid disorders, myeloid disorders, andAIDS associated leukemias.

Lymphoid disorders include but are not limited to acute lymphocyticleukemia and chronic lymphoproliferative disorders (e.g., lymphomas,myelomas, and chronic lymphoid leukemias). Lymphomas include, forexample, Hodgkin's disease, non-Hodgkin's lymphoma lymphomas, andlymphocytic lymphomas). Chronic lymphoid leukemias include, for example,T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.

The invention further relates to the use of the compounds according tothe invention or pharmaceutically acceptable salts or solvates thereoffor the prevention and/or treatment of radiation-induced fibrosis,connective tissue diseases (such as for example Sjogrën syndrome, i.e.scleroderma), chronic bacterial infection (such as for exampleHelicobacter Pylori), abnormal scarring (keloids) and polymicrobialsepsis.

The invention further relates to a method for treatment or prevention ofradiation-induced fibrosis, connective tissue diseases (such as forexample Sjogrën syndrome, i.e. scleroderma), chronic bacterial infection(such as for example Helicobacter Pylori), abnormal scarring (keloids)and polymicrobial sepsis, which comprises administering to a mammalianspecies in need thereof a therapeutically effective amount of thecompound according to the invention or a pharmaceutically acceptablesalt or solvate thereof.

The invention further provides the use of a compound of Formula I or apharmaceutically acceptable salt and solvate thereof for the manufactureof a medicament for treating and/or preventing radiation-inducedfibrosis, connective tissue diseases (such as for example Sjogrënsyndrome, i.e. scleroderma), chronic bacterial infection (such as forexample Helicobacter Pylori), abnormal scarring (keloids) andpolymicrobial sepsis.

The invention also provides for a method for delaying in patient theonset of radiation-induced fibrosis, connective tissue diseases (such asfor example Sjogrën syndrome, i.e. scleroderma), chronic bacterialinfection (such as for example Helicobacter Pylori), abnormal scarring(keloids) and polymicrobial sepsis, comprising the administration of apharmaceutically effective amount of a compound of Formula I orpharmaceutically acceptable salt and solvate thereof to a patient inneed thereof.

Formulations

The invention also provides pharmaceutical compositions comprising acompound of Formula I or a pharmaceutically acceptable salt and solvatethereof and at least one pharmaceutically acceptable carrier, diluent,excipient and/or adjuvant. As indicated above, the invention also coverspharmaceutical compositions which contain, in addition to a compound ofthe present invention, a pharmaceutically acceptable salt and solvatethereof as active ingredient, additional therapeutic agents and/oractive ingredients.

Another object of this invention is a medicament comprising at least onecompound of the invention, or a pharmaceutically acceptable salt andsolvate thereof, as active ingredient.

According to a further feature of the present invention there isprovided the use of a compound of Formula I or a pharmaceuticallyacceptable salt and solvate thereof for the manufacture of a medicamentfor modulating A2A activity in a patient, in need of such treatment,which comprises administering to said patient an effective amount ofcompound of the present invention, or a pharmaceutically acceptable saltand solvate thereof.

Generally, for pharmaceutical use, the compounds of the invention may beformulated as a pharmaceutical preparation comprising at least onecompound of the invention and at least one pharmaceutically acceptablecarrier, diluent, excipient and/or adjuvant, and optionally one or morefurther pharmaceutically active compounds.

By means of non-limiting examples, such a formulation may be in a formsuitable for oral administration, for parenteral administration (such asby intravenous, intramuscular or subcutaneous injection or intravenousinfusion), for topical administration (including ocular), foradministration by inhalation, by a skin patch, by an implant, by asuppository, etc. Such suitable administration forms—which may be solid,semi-solid or liquid, depending on the manner of administration—as wellas methods and carriers, diluents and excipients for use in thepreparation thereof, will be clear to the skilled person; reference ismade to the latest edition of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations includetablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes,lotions, soft and hard gelatin capsules, suppositories, drops, sterileinjectable solutions and sterile packaged powders (which are usuallyreconstituted prior to use) for administration as a bolus and/or forcontinuous administration, which may be formulated with carriers,excipients, and diluents that are suitable per se for such formulations,such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gumacacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethyleneglycol, cellulose, (sterile) water, methylcellulose, methyl- andpropylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetableoils and mineral oils or suitable mixtures thereof. The formulations canoptionally contain other substances that are commonly used inpharmaceutical formulations, such as lubricating agents, wetting agents,emulsifying and suspending agents, dispersing agents, desintegrants,bulking agents, fillers, preserving agents, sweetening agents, flavoringagents, flow regulators, release agents, etc. The compositions may alsobe formulated so as to provide rapid, sustained or delayed release ofthe active compound(s) contained therein.

The pharmaceutical preparations of the invention are preferably in aunit dosage form, and may be suitably packaged, for example in a box,blister, vial, bottle, sachet, ampoule or in any other suitablesingle-dose or multi-dose holder or container (which may be properlylabeled); optionally with one or more leaflets containing productinformation and/or instructions for use.

Depending on the condition to be prevented or treated and the route ofadministration, the active compound of the invention may be administeredas a single daily dose, divided over one or more daily doses, oressentially continuously, e.g. using a drip infusion.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A and FIG. 1B are graphs showing the percentage of cytokinesreleased in peripheral blood lymphocytes, in the presence of A2a agonistCGS24680, over the concentration of compound 7 of the present invention.FIG. 1A relates to whole blood cell cultures stimulated with LPS andFIG. 1B relates to whole blood cell cultures stimulated withanti-CD3/CD28.

FIG. 2 is a graph showing the percentage pCREB inhibition in peripheralblood lymphocytes over the concentration of compound 4 of the presentinvention.

FIG. 3 is a graph showing the percentage of cytotoxicity over the overthe concentration of compounds 4 and 31 of the present invention.

EXAMPLES

The present invention will be better understood with reference to thefollowing examples. These examples are intended to representative ofspecific embodiments of the invention, and are not intended as limitingthe scope of the invention.

The following abbreviations are used:

Boc: tert-Butoxycarbonyl,

BSA: Bis(trimethylsilyl)acetamide or bovine serum albumin, depending onthe context,

Cpd: Compound,

DavePhos: 2-Dicyclohexylphosphino-2′-biphenyl,

DCM: Dichloromethane,

DIPEA: N,N-Diisopropylethylamine,

DMF: Dimethylformamide,

DMSO: Dimethyl sulfoxide,

eq.: Equivalent(s),

EtOAc: Ethyl acetate,

g: Gram(s),

h: Hour(s),

HAS: Human serum albumin,

HPLC: High performance liquid chromatography,

HMDS: Hexamethyldisilazane,

L: Liter(s),

LCMS: Liquid chromatography-mass spetrometry

LHMDS: Lithium bis(trimethylsilyl)amide,

M: mol·L⁻¹,

MeOH: Methanol,

μg: Microgram(s),

μmol: Micromole(s),

μL: Microliter(s),

mg: Milligram(s),

mL: Milliliter(s),

mmol: Millimole(s),

mM: mmol·L⁻¹,

min: Minute(s),

mol: Mole(s),

N: Normality,

N₂: Nitrogen,

ng: Nanogram(s),

nM: nmol·L⁻¹,

NMP: N-Methyl-2-pyrrolidone,

NMR: Nuclear magnetic resonance spectroscopy,

quant.: Quantitative (yield),

SFC: Supercritical fluid chromatography,

rt or RT: Room temperature,

tBu: tert-Butyl,

TEA: Triethylamine,

TFA: Trifluoroacetic acid,

THF: Tetrahydrofuran,

TLC: Thin layer chromatography,

VTD: Vacuum tray drayer.

I. CHEMISTRY EXAMPLES

The MS data provided in the examples described below were obtained asfollows:

LCMS were recorded using Agilent 6130 or 6130B multimode (ESI+APCI).

LCMS Methods:

Column: XBridge C8 (50×4.6 mm) 5 μm; Method: A: 0.1% TFA in H₂O, B: 0.1%TFA in ACN, Flow Rate: 2.0 mL/min.

Column: Zorbax extend C18 (50×4.6 mm) 5 μm; Method: A: 10 mM NH₄OAc inH₂O, B: ACN, Flow Rate: 1.2 m/min.

Column: Zorbax XDB C18 (50×4.6 mm) 3.5 μm; Method: A: 0.1% HCOOH in H₂O,B: ACN, Flow Rate: 1.5 mL/min.

Column: XBridge C8 (50×4.6 mm) 3.5 μm; Method: A: 10 mM NH₄HCO₃ in H₂O,B: ACN, Flow Rate: 1.2 mL/min.

The NMR data provided in the examples described below were obtained asfollowed: 1H-NMR: Bruker DPX 400 MHz. Abbreviations for multiplicitiesobserved in NMR spectra are as follows: s (singlet), d (doublet), t(triplet), q (quadruplet), m (multiplet), br (broad).

HPLC Purity were evaluated with either of two methods:

Method XB0595TF; COLUMN: XBridge C8 (50×4.6) mm, 3.5 μm; Gradient ofeluents from 0.1% TFA in H₂O to 0.1% TFA in ACN, Flow Rate: 2.0 mL/min.

Method: AM9010A3; COLUMN: Phenomenex gemini NX—C18 (150×4.6), 3.0 μm;Gradient of eluents from 10 mM Ammonium acetate in water to ACN, FlowRate: 1.0 mL/min.

Method: XB0595NHC; COLUMN: XBridge C8 (50×4.6) mm, 3.5 μm; Gradient ofeluents from 10 mM Ammonium bicarbonate in water to ACN, Flow Rate: 1.0mL/min.

Solvents, reagents and starting materials were purchased and used asreceived from commercial vendors unless otherwise specified.

The intermediates and compounds described below were named usingChemBioDraw® Ultra version 12.0 (PerkinElmer).

I.1. Synthesis of Intermediate Compounds Intermediate 1:2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate

Step 1: 2,6-diamino-5-thiocyanatopyrimidin-4-ol: To a stirred solutionof Acetic acid (27500 mL) in a reactor at 25-30° C. under Nitrogenatmosphere was added 2, 6-diaminopyrimidin-4-ol (500 g). Potassiumthiocyanate (1586 g) was added slowly and the temperature was raised to90±5° C.; until the reaction mass becomes a clear solution. Once itbecomes a clear solution, the reaction mixture was cooled to 15±5° C.and bromine (633 g) in acetic acid (750 mL) was added drop wise, stirredfor 2 h at the same temperature. After the completion of the reaction,the reaction mixture was neutralised using aqueous ammonia (9000 mL) andstirred for 16 h at 20±5° C. The precipitate formed was filtered andrinsed with water (2500 mL) and methanol (1000 mL). The wet material wasdried in VTD at 70° C. for 24 hours to give the title compound as a paleyellow solid (206 g, quant). LCMS: 184.3 [M+1]⁺. ¹H-NMR (400 MHz,DMSO-d6): δ 10.36 (s, 1H), 7.03 (s, 2H), 6.64 (bs, 2H).

Step 2: 2,5-diaminothiazolo[4,5-d]pyrimidin-7-ol: To a stirred solutionof 2,6-diamino-5-thiocyanatopyrimidin-4-ol (Step-1) (750 g, 4.09 mol) inTHF (15 L) was added tetrabutylammonium fluoride (1 M in THF, 6750 mL)and the reaction mass was heated to 64±3° C. for 24 h. After thecompletion of the reaction, the reaction mixture was cooled to 25±5° C.for 1 h. The precipitate formed was filtered and rinsed with THF (2.25L). The wet solid was taken up in water (6 L) and concentratedhydrochloric acid (1.5 L) was added. The reaction mixture was stirredfor 4 h. The reaction mixture was filtered and the solid residue washedwith water (3.75 L) and suck dried for 1 h. The wet material was treatedwith water (6 L) and sodium bicarbonate (3 kg) was added. The reactionmass was stirred for 4 hours, filtered, washed with water (3.75 L) anddried in VTD for 16 h to afford the title compound as a yellow solid(580 g; 78%). LCMS: 184.2 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ 10.84 (s,1H), 7.89 (s, 2H), 6.46 (s, 2H).

Step 3: 5-amino-7-hydroxythiazolo[4,5-d]pyrimidin-2(3H)-one: A hot (80°C.) mixture of 2,5-diaminothiazolo[4,5-d]pyrimidin-7-ol (Step 2; 570 g,3.11 mol) and NaNO₂ (570 g, 8.26 mol) in water (5700 mL) was slowlyadded to a hot solution (80° C.) of Conc. HCl (11400 mL, 15 Vol). Thereaction mixture was stirred for 2 h and the completion of the reactionwas monitored by HPLC. After the completion of the reaction, the mixturewas cooled to 15° C. and basified to pH 12 with NaOH pellets. Thereaction mass was heated to 80° C. for 2 hours, then cooled to 35° C.and the pH was adjusted to 5-6 using concentrated hydrochloric acid. Thesolid precipitated was filtered washed with water (5V) and dried in VTDto afford the product as a Pale brown solid (286 g, 51%). LCMS: 185.6[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.08 (s, 1H), 11.10 (s, 1H), 6.88(s, 2H).

Step 4: 5-amino-3-(2-methoxyethyl)thiazolo[4,5-d]pyrimidine-2,7 (3H,4H)-dione: 5-amino-7-hydroxythiazolo[4,5-d]pyrimidin-2(3H)-one (36.2 g,0.196 mol, 1 eq) was taken in dry DMF (600 mL) and heated to 90° C. in asealed tube. The reaction mixture was stirred for 30 min at 90° C., thencooled to 30° C. To this reaction mixture was added 60% NaH (10.4 g, 1.1eq) slowly and stirred for 30 min followed by addition of1-bromo-2-methoxyethane (32.83 g, 1.1 eq). The reaction mixture wasagain heated to 100° C. The completion of the reaction was monitored byTLC. After the completion of the reaction, the reaction mixture wascooled to RT, concentrated completely and purified by columnchromatography using DCM/Methanol (90:10) to afford as a white solid (20g, 41%). LCMS: 243.6 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ 11.10 (s, 1H),6.92 (bs, 2H), 3.93 (t, J=6 Hz, 2H), 3.57 (t, J=6 Hz, 2H), 3.23 (s, 3H).

Step 5:5-amino-7-chloro-3-(2-methoxyethyl)thiazolo[4,5-d]pyrimidin-2(3H)-one:5-amino-7-hydroxy-3-(2-methoxyethyl)thiazolo[4,5-d]pyrimidin-2(3H)-one(10 μg, 0.0412 mol) was treated with POCl₃ (100 mL) and heated to 90° C.for 18 h in a sealed tube. After the completion of the reaction asmonitored by TLC, the reaction mixture was concentrated and ice coldwater was added. The pH of the reaction mixture was adjusted to 7 usingNaHCO₃ and extracted with DCM. The organic layer was separated, driedover Na₂SO₄, filtered and concentrated to afford a pale yellow solidwhich was used as such for the next step without further purification(6.8 g, 63%). LCMS: 261.2 [M+1]⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.37 (s,2H), 4.01 (t, J=5.6 Hz, 2H), 3.62 (t, J=5.6 Hz, 2H), 3.23 (s, 3H).

Step 6:N′-(5-amino-3-(2-methoxyethyl)-2-oxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7-yl)furan-2-carbohydrazide:5-amino-7-chloro-3-(2-methoxyethyl)thiazole[4,5-d]pyrimidin-2(3H)-one(6.8 g, 0.026 mol) in ethanol was added furoic acid hydrazide (4.9 g,0.039 mol) and heated to 100° C. in a sealed tube for 19 h. The reactionwas monitored by TLC. After the completion of the reaction, the reactionmixture was cooled to RT, concentrated under reduced pressure. To thisresidue, Petroleum Ether was added to afford a solid which was filteredand was used as such for the next step without further purification (7.2g, 79%). LCMS: 351.2 [M+1]⁺.

Step 7:5-amino-8-(furan-2-yl)-3-(2-methoxyethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one:N′-(5-amino-3-(2-methoxyethyl)-2-oxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7-yl)furan-2-carbohydrazide(7.2 g, 0.20 mol) was treated with BSA (50.8 mL, 11 eq) and HMDS (76 mL,25 eq). The reaction mixture was heated to 127° C. for 20 h. After thecompletion of reaction, the reaction mixture was cooled to 0° C. andmethanol (30 mL) was added. The solid which precipitated out wasfiltered and washed with Petroleum ether to afford an Off-White Solidwhich was used as such for the next step without further purification(5.9 g, 87%). LCMS: 333.2 [M+1]⁺.

Step 8:5-amino-8-(furan-2-yl)-3-(2-hydroxyethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one:To a solution of5-amino-8-(furan-2-yl)-3-(2-methoxyethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (5.9 g, 0.017 mol) in dry DCM (100 mL) at −50° C.,was added BBr₃ (11.5 g, 2.6 eq) slowly and maintained for 19 h at 25-30°C. The reaction was monitored by TLC. After the completion of reaction,the reaction mixture was quenched with chilled water (100 mL) thenneutralized with 10% Sodium bicarbonate solution, filtered and washedwith water to afford a pale yellow solid which was used as such for thenext step without further purification (3.6 g, 65%). LCMS: 319.2 [M+1]⁺.¹H-NMR (400 MHz, DMSO-d₆): δ 8.31 (s, 2H), 7.95 (d, J=0.8 Hz, 1H), 7.24(t, J=2.8 Hz, 1H), 6.74-6.74 (m, 1H), 4.94 (t, J=5.6 Hz, 1H), 4.01 (t,J=6.4 Hz, 2H), 3.71 (t, J=6.0 Hz, 2H).

Step 9:2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate:5-amino-8-(furan-2-yl)-3-(2-hydroxyethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (3.6 μg, 0.011 mol) was dissolved in dry DMF (95 mL) at 60° C.till the reaction mixture became clear. The reaction mass was cooled to0° C. and TEA (3 g, 3 eq) was added, followed by Mesyl chloride (1.6 g,1.3 eq). The reaction mixture was stirred at RT for 48 h. After thecompletion of reaction, ethyl acetate (100 mL) & water (50 mL) was addedand extracted. The organic layer was dried over Na₂SO₄, filtered andevaporated to afford the compound as a yellow solid which wasanalytically pure to be used for the next step (3.0 g, 67%). LCMS: 397.2[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.37 (s, 2H), 7.95 (s, 1H), 7.25(d, J=3.6 Hz, 1H), 6.74-6.74 (m, 1H), 4.56 (t, J=5.2 Hz, 2H), 4.26 (t,J=4.8 Hz, 2H), 3.16 (s, 3H).

Intermediate 2:2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)-acetaldehyde

To a stirred solution of5-amino-8-(furan-2-yl)-3-(2-hydroxyethyl)thiazolo[5,4-e][1,2,4]triazolo-[1,5-c]pyrimidin-2(3H)-one(prepared according to the protocol described for Intermediate 1, Step8, 3.6 g, 10.74 mmol) in THF (150 mL) was added a solution of IBX (15.04g, 53.72 mmol) in DMSO (35 mL). The resulting mixture was stirred at RTfor 6 h. The reaction mixture was diluted with DCM and the layers wereseparated. The organic layer was washed successively with saturatedNaHCO₃ solution and saturated brine solution. Then it was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude residue (3.0 g, 75%) obtained was used for next step withoutfurther purification. LCMS 317 [M+1]⁺.

I.2. SYNTHESIS OF FINAL COMPOUNDS Example 1:3-(2-(4-(4-((1H-1,2,3-triazolo-4yl)methoxy-2fluorophenyl)piperazine-1-yl)ethyl)-5-amino-(8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-2(3H)-one

Step 1: tert-butyl 4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate(2): To a mixture of 4-Bromo-3-fluorophenol (10 g, 0.052 mol),tert-butyl piperazine-1-carboxylate (11.70 g, 0.063 mol), DavePhos(0.515 g, 0.001 mol) and Pd₂(dba)₃ (0.958 g, 0.001 mol) was added LHMDS(115 mL of 1.0 M solution in THF, 0.115 mol) at 0° C. under nitrogen.The reaction mixture was heated at 65° C. for 24 h and monitored by TLC.The crude reaction mixture was neutralized with saturated NH₄Cl andextracted with ethyl acetate (2×100 mL). The combined organic layer wasconcentrated and purified by column chromatography to afford the titlecompound as off white solid (2.25 g, 14.5%). LCMS (ESI positive ion)m/z: calculated: 296.15; observed: 297.2 (M+1).

Step 2: tert-butyl4-(2-fluoro-4-(prop-2-yn-1-yloxy)phenyl)piperazine-1-carboxylate (3): Toa stirred suspension of sodium hydride (0.7 g, 0.0304 mol) in DMF (10mL) was added tert-butyl hydroxyphenyl)piperazine-1-carboxylate (2, 4.5g, 0.0152 mol) in DMF (20 mL) at 0° C. under nitrogen. The reactionmixture was stirred for 15 min at 0° C. and then propargyl bromide (2.71g, 0.0228 mol) in DMF (10 mL) was added and stirred for 16 h at RT.After the reaction completion (TLC), the reaction mixture was treatedwith saturated NH₄Cl (20 mL) and extracted with ethyl acetate. Organiclayer was washed with saturated brine solution, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudeobtained was purified by column chromatography (40% EtOAc/Hexane aseluent) to afford tert-butyl4-(2-fluoro-4-(prop-2-yn-1-yloxy)phenyl)piperazine-1-carboxylate asbrown gummy liquid (3.6 g, 70.8%). LCMS (ESI positive ion) m/z:calculated: 334.17; observed: 335.2 (M+1).

Step 3: 1-(2-fluoro-4-(prop-2-yn-1-yloxy)phenyl) piperazine (4): To astirred solution of tert-butyl4-(2-fluoro-4-(prop-2-yn-1-yloxy)phenyl)piperazine-1-carboxylate (3, 3.6g, 10.8 mmol) in dichloromethane (15 mL) at 0° C., 4 N HCl in dioxane(20 mL) was added dropwise and stirred at RT for 4 h. After the reactioncompletion (TLC), the reaction mixture was concentrated under reducedpressure. The salt was neutralised with sodium bicarbonate solution,extracted with DCM and the combined organic layers were washed withbrine, dried over sodium sulphate and then concentrated under reducedpressure to afford 1-(2-fluoro-4-(prop-2-yn-1-yloxy)phenyl)piperazine asbrown solid (2.5 g, 99.2%); LCMS (ESI positive ion) m/z: calculated:234.12; observed: 235.2 (M+1).

Step 4:5-amino-3-(2-(4-(2-fluoro-(prop-2yn-1-yloxy)phenyl)piperazine-1-yl)ethyl)-8-(furan-2-yl)thaizolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-2(3H)-one(5): To a mixture of 1-(2-fluoro-4-(prop-2-yn-1-yloxy)phenyl)piperazine(4, 1 g, 4.3 mmol) and2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (0.9 g, 2.2 mmol) in N,N-Dimethylformamide (15 mL),was added DIPEA (0.6 mL, 6.8 mmol) and the reaction mixture was stirredat 120° C. for 16 h. After completion of the reaction (TLC & LCMS), thereaction mass was concentrated under reduced pressure. The crude productwas washed with mixture of diethyl ether and acetonitrile to afford5-amino-3-(2-(4-(2-fluoro-4-(prop-2yn-1-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-oneas brown solid (0.7 g, 57.8%); HPLC purity (XB0595TF): 92.63%; LCMS (ESIpositive ion) m/z: calculated: 534.16; observed: 534.8 (M+1).

Step 5:3-(2-(4-(4-((1H-1,2,3-triazolo-4yl)methoxy-2fluorophenyl)piperazine-1-yl)ethyl)-5-amino-(8-(furan-2-yl)thaizolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-2(3H)-one(Compound 1): To a stirred solution of5-amino-3-(2-(4-(2-fluoro-4-(prop-2yn-1-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(5, 0.4 g, 0.7 moles) in DMF (4.5 mL) and MeOH (0.5 mL) was added copperiodide (0.030 g, 0.014 mmol) at RT. To the reaction mixturetrimethylsilyl azide (0.2 mL, 1.4 mmol) was added dropwise undernitrogen atmosphere at 0° C. and was heated to 100° C. for 16 h. Afterthe reaction completion (TLC), the reaction mixture was extracted withethyl acetate (2×20 mL) and the combined organic layers were washed withbrine, dried over sodium sulphate and concentrated under reducedpressure. The product was further enriched by washing with diethyl etherand acetonitrile (50:50) to afford compound 1:3-(2-(4-(4-((1H-1,2,3-triazol-4-yl)methoxy)-2-fluorophenyl)-piperazin-1-yl)ethyl)-5-amino-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-oneas brown solid (0.115 g, 26.6%). HPLC purity (XB0595TF): 92.08%; LCMS(ESI positive ion) m/z: calculated: 577.18; observed: 578.0 (M+1);¹H-NMR (400 MHz, DMSO-d6): δ 15.12 (brs, 1H), 8.32 (brs, 2H), 7.96 (s,2H), 7.24 (d, J=3.2 Hz, 1H), 6.96-6.89 (m, 2H), 6.79-6.73 (m, 2H), 5.13(s, 2H), 4.08 (t, J=6.0 Hz, 2H), 2.86 (m, 4H), 2.72-2.63 (m, 6H).

Example 2:5-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)methyl)-1,3,4-oxadiazol-2(3H)-one

Step 1: tert-butyl4-(4-(2-ethoxy-2-oxoethoxy)-2-fluorophenyl)piperazine-1-carboxylate (2):To a stirred solution of tert-butyl4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (1, 2 g, 6.75 mmol)and ethyl bromoacetate (1.67 g, 10.0 mmol) in N,N-Dimethylformamide (15mL), was added K₂CO₃ (2.76 g, 20.0 mmol) and the reaction mixture washeated at 90° C. for 16 h. After the reaction completion (TLC), thereaction mixture was diluted with water (20 mL) and extracted with ethylacetate. Organic layer was washed with saturated brine solution, driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The crude obtained was purified by column chromatography (20%EtOAc/Hexane as eluent) to afford the product as brown liquid (1.9 g,73.6%); LCMS (ESI positive ion) m/z: calculated: 382.19; observed: 383.0(M+1).

Step 2: ethyl 2-(3-fluoro-4-(piperazin-1-yl)phenoxy)acetate (3): To anice cold solution of tert-butyl4-(4-(2-ethoxy-2-oxoethoxy)-2-fluorophenyl)piperazine-1-carboxylate (2,1.9 g, 5.0 mmol) in dichloromethane, 4 N HCl in Dioxane (15 mL) wasadded and the reaction mixture was stirred at RT for 5 h. After thecompletion of reaction (TLC), reaction mass was quenched with saturatedsodium bicarbonate solution and was extracted with ethyl acetate.Organic layer was dried over sodium sulphate, filtered and concentratedunder reduced pressure to afford the product as brown liquid (1.00 g,71.4%); LCMS (ESI positive ion) m/z: calculated: 282.14; observed: 283.1(M+1).

Step 3: ethyl2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)acetate(4): To a mixture of ethyl 2-(3-fluoro-4-(piperazin-1-yl)phenoxy)acetate(3, 1.0 g, 3.52 mmol) and2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (1.12 μg, 2.82 mmol) in N,N-Dimethylformamide (15 mL),was added DIPEA (1.3 g, 11.0 mmol) and the reaction mixture was stirredat 120° C. for 16 h. After the completion of reaction (TLC & LCMS), thesolvent was removed under reduced pressure and purified byrecrystallization with diethyl ether: acetonitrile (1:1) mixture to getthe title compound as dark brown solid (0.70 g, 42.5%); LCMS (ESIpositive ion) m/z: calculated: 582.18; observed: 583.0 (M+1).

Step 4:2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)acetohydrazide(5): To a solution of Ethyl2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]-triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)acetate(4, 0.2 g, 0.34 mmol) in ethanol (20 mL), was added hydrazine hydrate(50 mg, 1.0 mmol) and the reaction mixture was stirred at 90° C. for 16h. After the completion of reaction (TLC & LCMS), the solvent wasremoved under reduced pressure and purified by recrystallization withdiethylether and acetonitrile mixture to get the title compound as whitesolid (150 mg, 76.9%); LCMS (ESI positive ion) m/z: calculated: 568.18;observed: 569.0 (M+1).

Step 5:5-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]tri-azolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)methyl)-1,3,4-oxadiazol-2(3H)-one(Compound 2): To a suspension of compound 5 (0.158 g, 0.27 mol) in1,4-Dioxane (10 mL) and DMF (1 mL), TEA (0.084 g, 0.83 mol) was addedand the reaction mixture was stirred at 100° C. for 4 h. After thecompletion of reaction (TLC & LCMS), solvent was removed under reducedpressure and purified by prep. HPLC purification to get title compound 2as white solid (21 mg, 12.7%); HPLC purity (XB0595TF): 95.33%; LCMS (ESIpositive ion) m/z: calculated: 594.16; observed: 595.1 (M+1); ¹H-NMR(400 MHz, DMSO-d6): δ 12.52 (brs, 1H), 8.32 (brs, 2H), 7.96 (d, J=0.80Hz, 1H), 7.25 (d, J=3.20 Hz, 1H), 6.99-6.92 (m, 2H), 6.78 (dd, J=2.0 &8.8 Hz, 1H), 6.74 (dd, J=1.6 & 3.2 Hz, 1H), 5.01 (s, 2H), 4.08 (t,J=6.40 Hz, 2H), 2.87 (m, 4H), 2.72-2.63 (m, 6H).

Example 3:5-amino-3-(2-(4-(3-fluoropyridin-4-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: 1-(3-fluoropyridin-4-yl)piperazine (3): To a stirred solution of3-fluoro-4-iodopyridine (2, 2 g, 4.48 mmol, 1 eq) in NMP (20 mL), DIPEA(0.694 g, 5.38 mmol, 1.2 eq) and piperazine (1, 0.484 g, 6.72 mmol, 1.5eq) were added at RT. The resulting mixture was stirred at 80° C. for 16h. After the completion, the reaction mixture was concentrated underreduced pressure. The residue was taken in water and lyophilized. Thegummy solid obtained was triturated with diethyl ether and n-pentane toafford 1-(3-fluoropyridin-4-yl)piperazine, 3 (0.750 g, 92%) as lightyellow colour solid. LCMS (ESI positive ion) m/z: calculated: 181.21;Observed; 182.2 (M+1).

Step 2:5-amino-3-(2-(4-(3-fluoropyridin-4-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 3): To a solution of 1-(3-fluoropyridin-4-yl)piperazine (3,0.071 g, 0.392 mmol, 1 eq) in DMF (2 mL),2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[4,5-e][1,2,4]triazolo[1,5-c]-pyrimidin-1(2H)-yl)ethylmethane sulfonate (4, 0.150 g, 0.392 mmol, 1.03 eq) and DIPEA (0.100 g,0.775 mmol, 2 eq) was added at RT. The reaction was stirred at 80° C.for 16 h. After completion, the reaction mixture was concentrated underreduced pressure. The residue obtained was diluted with water andextracted with ethyl acetate (2×30 mL). Combined organic phases weredried (anhydrous Na₂SO₄), filtered and concentrated under reducedpressure. The crude product obtained was purified by reverse phasepreparative HPLC to afford title compound 3 as brown colour solid (0.013g, 7%). LCMS (ESI positive ion) m/z: calculated: 481.51; Observed; 482(M+1). HPLC purity (XB0595TF.M): 97.75%.

Example 4:2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetamide

Step 1: Preparation of 1-(benzyloxy)-5-bromo-2,4-difluorobenzene (2): Toa solution of 5-bromo-2,4-difluorophenol (1, 20 g, 95.69 mmol) andbenzyl bromide (18 g, 105.26 mmol) in N,N-dimethylformamide (200 mL),was added K₂CO₃ (39.62 g, 287.08 mmol) and the reaction mixture washeated at 90° C. for 16 h. After the reaction completion (TLC), thereaction mixture was diluted with water (200 mL) and extracted withethyl acetate. Organic layer was washed with saturated brine solution,dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude obtained was purified by column chromatography (5%EtOAc/Hexane as eluent) to afford the product as off white solid (24 g,85%). LCMS (ESI negative ion); m/z: calculated: 297.98; Observed; 296.8(M−1); ¹H-NMR (400 MHz, DMSO-d6): δ 7.60-7.67 (m, 1H), 7.55-7.58 (m,1H), 7.37-7.44 (m, 5H), and 5.20 (s, 2H).

Step 2: Preparation of tert-butyl4-(5-(benzyloxy)-2,4-difluorophenyl)piperazine-1-carboxylate (3): To asolution of 1-(benzyloxy)-5-bromo-2,4-difluorobenzene (2, 24 g, 80.08mmol), N-Boc piperazine (16.55 g, 88.88 mmol) and sodium tert-butoxide(17.06 g, 177.77 mmol) in toluene (200 mL), t-Bu Xphos (3.43 g, 8.08mmol) were added. The reaction mixture was purged with N₂ and Pd₂(dba)₃(3.69 g, 4.04 mmol) was added. The reaction mixture was heated at 115°C. for 16 h and after completion (TLC), the reaction mixture was cooledand filtered through celite. The filtrate was concentrated and purifiedby column chromatography (12-15% EtOAc/Hexane) to get the title compoundas light brown oil (18 g, 55.14%); LCMS (ESI positive ion); m/z:calculated: 404.19; Observed; 405 (M+1); ¹H-NMR (400 MHz, DMSO-d6): δ7.34-7.38 (m, 5H), 7.26 (t, J=11.60 Hz, 1H), 6.94 (t, J=8.80 Hz, 1H),5.16 (s, 2H), 3.45 (m, 4H), 2.90 (t, J=4.8 Hz, 4H), and 1.42 (s, 9H).

Step 3: tert-butyl4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (4): To a clearsolution of tert-butyl4-(5-(benzyloxy)-2,4-difluorophenyl)piperazine-1-carboxylate (3, 18 g,44.55 mmol) in ethanol (180 mL), 10% Pd—C(2.7 g, 15% Wt.) was added andthe reaction mixture was stirred under H₂ atmosphere at RT for 5 h.After completion (TLC), the reaction mixture was filtered through celiteand washed with methanol (500 mL). The filtrate was concentrated andtriturated with diethyl ether to get the title compound as off whitesolid (13 g, 92.6%); LCMS (ESI positive ion); m/z: calculated: 314.14;Observed; 315.2 (M+1); ¹H-NMR (400 MHz, CD₃OD): δ 6.92 (t, J=8.8 Hz,1H), 6.56-6.51 (m, 2H), 3.57 (m, 4H), 2.91 (t, J=4.80 Hz, 4H), and 1.49(s, 9H).

Step 4: tert-butyl4-(5-(2-amino-2-oxoethoxy)-2,4-difluorophenyl)piperazine-1-carboxylate(5): To a suspension of tert-butyl4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (4, 10 g, 31.7mmol) and bromoacetamide (5.25 g, 38.09 mmol) in N,N-Dimethyl formamide(100 mL), K₂CO₃ (13.14 g, 95.23 mmol) was added. The reaction mixturewas stirred at 90° C. for 5 h and monitored by TLC. After completion,the reaction mixture was diluted with water (100 mL) and the crudeproduct was extracted with ethyl acetate. Organic layer was washed withsaturated brine solution, dried over anhydrous Na₂SO₄, filtered,concentrated and triturated with diethyl ether to get the title compoundas off light brown solid (9.5 g, 80.7%); LCMS (ESI positive ion); m/z:calculated: 371.17; Observed; 372.2 (M+1); ¹H-NMR (400 MHz, CDCl₃): δ6.92 (t, J=11.2 Hz, 1H), 6.92 (m, 2H), 5.66 (brs, 1H), 4.53 (s, 2H),3.61 (t, J=5.20 Hz, 4H), 2.98 (t, J=4.40 Hz, 4H), and 1.51 (s, 9H).

Step 5: 2-(2, 4-difluoro-5-(piperazin-1-yl)phenoxy)acetamide (6): To anice cold solution of tert-butyl4-(5-(2-amino-2-oxoethoxy)-2,4-difluorophenyl)-piperazine-1-carboxylate(5, 8.0 g, 21.5 mmol) in DCM, 4 N HCl in Dioxane (80 mL) was added andthe reaction mixture was stirred at RT for 5 h. After completion of thereaction (TLC), the HCl salt was filtered. The salt was dissolved inmethanol and neutralized using Tosic acid scavenger resin to get thefree base as the off white solid (3.5 g, 59.9%); LCMS (ESI positiveion); m/z: calculated: 271.11; Observed; 272.1 (M+1); ¹H-NMR (400 MHz,DMSO-d6): δ 7.49 (brs, 1H), 7.43 (brs, 1H), 7.25 (t, J=11.60 Hz, 1H),6.75 (t, J=8.80 Hz, 1H), 4.51 (s, 2H), and 2.81-2.86 (m, 8H).

Step 6:2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetamide(Compound 4): To a mixture of2-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)acetamide (6, 3.5 μg, 12.91μmmol) and2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)-ethylmethane sulfonate (5.88 g, 14.84 mmol) in N,N-Dimethyl formamide (70mL), was added DIPEA (8.33 g, 64.57 mmol) and the reaction mixture wasstirred at 120° C. for 16 h. After completion of the reaction (TLC &LCMS), the reaction mass was concentrated to half of the volume underreduced pressure and cooled to 0° C. The product was precipitated aspale yellow solid. It was filtered and dried. As the purity was notgood, it was suspended in DMSO (150 mL) and heated at 110° C. for 1 hand filtered in hot condition. The filtrate was cooled to 0° C., dilutedwith MeOH and then water was added slowly to facilitate theprecipitation. The mixture was stirred at RT for 1 h and filtered. Thesolid was washed with water and methanol to get compound 4 as lightyellow solid (2.5 g, 34%). HPLC purity (XB_0595TF.M): 92.4%; LCMS (ESIpositive ion) m/z: calculated: 571.16; Observed; 572.0 (M+1); ¹H-NMR(400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (t, J=0.8 Hz, 1H), 7.44 (brs,1H), 7.40 (brs, 1H), 7.27-7.21 (m, 2H), 6.76-6.72 (m, 2H), 4.49 (s, 2H),4.08 (t, J=6.0 Hz, 2H), 2.90 (m, 4H), 2.71 (t, J=6.00 Hz, 2H), and 2.63(m, 4H).

Examples 5 and 6:(S)-5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-oneand(R)-5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)-piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of tert-butyl4-(2-fluoro-4-(2-(methylthio)ethoxy)phenyl)piperazine-1-carboxylate (2):To a solution of tert-butyl4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (1, 0.3 g, 1.102mmol, 1 eq) and 1-chloro-2-methylsulfanyl-ethane (0.168 μg, 1.519 μmmol,1 eq) in N,N-dimethylformamide (3 mL), K₂CO₃ (0.419 g, 3.027 mmol, 2 eq)was added and the reaction mixture was heated at 90° C. for 16 h. Afterthe reaction completion (TLC), the reaction mixture was diluted withwater (10 mL) and extracted with ethyl acetate. Organic layer was washedwith saturated brine solution, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude residue obtained waspurified by column chromatography (50% EtOAc/Hexane as eluent) to affordthe product as off white solid (0.3 g, 53%). LCMS (ESI positive ion)m/z: calculated: 370.48; Observed; 370.9 (M+). 1H-NMR (400 MHz,DMSO-d6): δ 7.02 (m, 1H), 6.85 (m, 1H), 6.72 (m, 1H), 4.09-4.12 (m, 2H),3.45 (d, J=4.40 Hz, 4H), 2.80-2.86 (m, 6H), 2.14 (s, 3H), and 1.42 (s,9H).

Step 2: Synthesis of tert-butyl4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazine-1-carboxylate(3, 4): To an ice cold solution of tert-butyl4-(2-fluoro-4-(2-(methylthio)ethoxy)phenyl)piperazine-1-carboxylate (2,0.3 g, 0.809 mmol, 1 eq) in acetic acid (10 mL), hydrogen peroxide(0.187 mL) was added drop wise and stirred at same temperature for 2 h.After the reaction of completion (TLC), the reaction mixture poured into 4N NaOH solution (20 mL) and extracted with ethyl acetate. Organiclayer was washed with saturated brine solution, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudeobtained was purified by column chromatography (80% EtOAc/Hexane aseluent) to afford the product as off white solid. (0.29 g, 93%). LCMS(ESI positive ion) m/z: calculated: 386.48; Observed; 387.9 (M+1).1H-NMR (400 MHz, DMSO-d6): δ 7.02-7.04 (m, 1H), 6.88-6.92 (m, 1H),6.75-6.78 (m, 1H), 4.28-4.35 (m, 2H), 3.45 (d, J=4.52 Hz, 4H), 3.21-3.27(m, 1H), 3.00-3.05 (m, 1H), 2.85-2.87 (m, 4H), 2.63 (s, 3H), and 1.41(s, 9H).

Racemic mixture (0.29 g) was subjected to chiral separation by SFC (0.29g sample was dissolved in 3 mL of methanol), column—Lux A1 mobile phase:70:30 (A: B), A=liquid CO₂, B=methanol, flow rate: 0.9 mL/min; wavelength: 220 nm) to yield 130 mg of peak 1 (3) and 130 mg of peak 2 (4)as off white solid respectively. Note: Peak 1 from SFC purification wasarbitrarily considered as (S) isomer and peak 2 was considered as (R)isomer.

Synthesis of Compound 5

Step 3: Synthesis of(S)-1-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazine (5): To anice cold solution of tert-butyl(S)-4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)-piperazine-1-carboxylate(3, 0.13 g) in dichloromethane (1 mL), 4M HCl in dioxane (1 mL) wasadded and the reaction mixture was stirred at 0° C. for 1 h. Aftercompletion, the reaction mixture was concentrated under reduced pressureat room temperature. The residue obtained was triturated with diethylether. Then it was dissolved in methanol, passed through Si-Carbonateresin for making free base 5 (0.094 g, 59%). LCMS (ESI positive ion)m/z: calculated: 286.37; Observed; 287 (M+1).

Step 4: Synthesis of(S)-5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)-piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 5): A mixture of2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (7, 0.11 g, 0.303 mmol, 1 eq),(S)-1-(2-fluoro-4-(2(methylsulfinyl)-ethoxy)phenyl)piperazine (5, 0.094g, 0.33 mmol, 1.1 eq) and diisopropyl ethyl amine (0.195 g, 1.514 mmol,5 eq) in N,N-dimethylformamide (2 mL) was stirred at 120° C. for 16 h.The reaction progress was monitored by TLC. After completion, thereaction mixture was diluted with water (10 mL) and extracted with ethylacetate. Organic layer was washed with saturated brine solution, driedover anhydrous Na₂SO₄, filtered, concentrated. The crude residueobtained was subjected to preparative HPLC purification to affordcompound 5 as off white solid (5 mg). LCMS (ESI positive ion) m/z:calculated: 586.66; Observed; 587.2 (M+1). HPLC purity (XB0595TF.M):91.67%. 1H-NMR (400 MHz, DMSO-d6): δ 8.32 (s, 2H), 7.95-7.96 (m, 1H),7.24-7.25 (m, 1H), 6.93-6.98 (m, 1H), 6.85-6.89 (m, 1H), 6.73-6.74 (m,2H), 4.25-4.30 (m, 2H), 4.09 (s, 2H), 3.22-3.27 (m, 1H), 3.02 (m, 1H),2.87 (m, 5H), and 2.63 (m, 8H).

Synthesis of Compound 6

Step 1: (R)-1-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazine(6): To an ice-cold solution of tert-butyl(R)-4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)-phenyl)piperazine-1-carboxylate(4, 0.13 g,) in dichloromethane (1 mL), 4M HCl in dioxane (0.5 mL) wasadded and the reaction mixture was stirred at 0° C. for 1 h. Aftercompletion (TLC), the reaction mixture was concentrated under reducedpressure at room temperature. The crude residue obtained was trituratedwith diethyl ether. Then it was dissolved in methanol, passed throughSi-Carbonate resin for making free base 6, (0.094 g). LCMS (ESI positiveion) m/z: calculated: 286.37; Observed; 287 (M+1).

Step 2:(R)-5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)-piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 6): A mixture of2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (7, 0.11 g, 0.303 mmol, 1 eq),(R)-1-(2-fluoro-4-(2-(methylsulfinyl)-ethoxy)phenyl)piperazine (6, 0.094g, 0.33 mmol, 1.1 eq) and diisopropyl ethyl amine (0.195 g, 1.514 mmol,5 eq) in N,N-dimethylformamide (2 mL) was stirred at 120° C. for 16 h.The reaction progress was monitored by TLC. After completion, thereaction mixture was diluted with water (10 mL) and extracted with ethylacetate. Organic layer was washed with saturated brine solution, driedover anhydrous Na₂SO₄, filtered, concentrated. The crude productobtained was subjected to reverse phase preparative HPLC purification toafford compound 6 as off white solid. (3 mg). LCMS (ESI positive ion)m/z: calculated: 586.66; Observed; 587.2 (M+1). HPLC purity(XB0595TF.M): 96.6%. 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (broad s, 2H),7.95-7.95 (s, 1H), 7.24-7.25 (m, 1H), 7.00-6.88 (m, 1H), 6.85 (m, 1H),6.71-6.74 (m, 2H), 4.25-4.31 (m, 2H), 4.08 (t, J=6.00 Hz, 2H), 3.22-3.29(m, 2H), 3.00-3.03 (m, 1H), 2.86 (s, 4H), and 2.62-2.70 (m, 8H).

Examples 7, 8a and 8b:(R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)-phenyl)-piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]-pyrimidin-2(3H)-one,(+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-oneand(−)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of tert-butyl4-(2,4-difluoro-5-(2-(methylthio)ethoxy)-phenyl)piperazine-1-carboxylate(2): To a solution of tert-butyl4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (1, 0.5 g,1.591 mmol, 1 eq) and 1-chloro-2-methylsulfanyl-ethane (0.264 g, 2.386mmol, 1.5 eq) in N,N-dimethylformamide (5 mL), K₂CO₃ (0.439 g, 3.181mmol, 2 eq) was added and the reaction mixture was heated at 90° C. for16 h. After the reaction completion (TLC), the reaction mixture wasdiluted with water (10 mL) and extracted with ethyl acetate. Organiclayer was washed with saturated brine solution, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudeobtained was purified by column chromatography (50% EtOAc/Hexane aseluent) to afford the product as off white solid (2, 0.5 g, 77%). LCMS(ESI positive ion) m/z: calculated: 388.47; Observed; 389 (M+1).

Step 2: Synthesis of tert-butyl4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)-piperazine-1-carboxylate(3, 4): To an ice cold solution of tert-butyl4-(2,4-difluoro-5-(2-(methylthio)ethoxy)-phenyl)piperazine-1-carboxylate(2, 0.5 g, 0.001 mmol, 1 eq) in acetic acid (10 mL), hydrogen peroxide(0.312 mL) was added drop wise and stirred at same temperature for 2 h.After the reaction completion (TLC), the reaction mixture poured in to4N NaOH solution (20 mL) and extracted with ethyl acetate. Organic layerwas washed with saturated brine solution, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude obtained waspurified by column chromatography (80% EtOAc/Hexane as eluent) to affordthe product as off white solid (0.38 g, 86%). LCMS (ESI positive ion)m/z: calculated: 404.47; Observed; 348.9 (M-t-butyl). 1H-NMR (400 MHz,DMSO-d6): δ 7.24-7.32 (m, 1H), 6.89-6.94 (m, 1H), 4.39-4.45 (m, 2H),3.47 (s, 4H), 3.05 (m, 2H), 2.94 (s, 4H), 2.64 (s, 3H), and 1.42 (s,9H). The above racemic compound (0.38 g) was subjected to chiralseparation by SFC (0.38 g sample was dissolved in 5 mL of methanol,column—Lux A1 mobile phase: 70:30 (A: B), A=liquid CO₂, B=methanol, flowrate: 0.9 mL/min; wave length: 220 nm) to yield 150 mg of peak 1 (3,[α]_(D)=+50.7°, c=1.1, MeOH) and 150 mg of peak 2 (4, [α]_(D)=−45.2°,c=1.1, MeOH) as off white solids respectively.

Step 3: Synthesis of(R,S)-1-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine(5RS): To an ice cold solution of tert-butyl(R,S)-4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)-piperazine-1-carboxylate(racemic mixture of 3 and 4, 0.15 g, 0.371 mmol, 1 eq) indichloromethane (2 mL), 4M HCl in dioxane (0.5 mL) was added and thereaction mixture was stirred at 0° C. for 1 h. After completion (TLC),the reaction mixture was concentrated under reduced pressure at roomtemperature. The residue obtained was triturated with diethyl ether toafford the racemic product. Then it was dissolved in methanol, passedthrough Si-Carbonate resin for making free base (0.09 g). LCMS (ESIpositive ion) m/z: calculated: 304.36; Observed; 305 (M+1).

Step 4 for Compound 7: Synthesis of(R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)-phenyl)-piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]-pyrimidin-2(3H)-one:To a solution of2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (6, 105 mg, 0.265 mmol, 1.0 eq) in DMF (2 mL),(R)-1-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine (5RS,86.46 mg, 0.278 mmol) and DIPEA (170.85 mg, 0.001 mmol, 5 eq) wereadded. The reaction mass was degassed with nitrogen and heated to 120°C. for 16 h. The progress of the reaction was monitored by LCMSanalysis. After completion, the reaction mixture was concentrated underreduced pressure. The crude product obtained was purified by gracecolumn chromatography with 5% Methanol in DCM to afford the requiredracemic compound. It was purified further by preparative HPLC to affordtitle compound 7 (6 mg, purity 96%). LCMS (ESI positive ion) m/z:calculated: 604.65; Observed; 605.2 (M+1). HPLC purity (XB0595TF.M):96.68%. 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 7.50 (m, 1H),7.27-6.97 (m, 3H), 6.83 (m, 1H), 6.73-6.74 (m, 1H), 4.36-4.45 (m, 2H),4.08 (m, 2H), 3.25-3.38 (m, 2H), 3.00-3.06 (m, 2H), 2.94 (s, 3H),2.63-2.71 (m, 2H), and 2.53-2.58 (m, 6H).

Step 3′: Synthesis of(+)-1-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine: To anice cold stirred solution of tert-butyl(+)-4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)-phenyl)piperazine-1-carboxylate(4, 500 mg, 1.23 mmol) in ethyl acetate (3 mL), SnCl₄ (644 mg, 2.47mmol) was added. The resulting mixture was stirred at RT for 2 h. Thereaction mixture was concentrated under reduced pressure. The residueobtained was triturated with cold ethyl acetate (2×10 mL) to afford thecrude product (580 mg), which was used as such for the next step. LCMS(M+H) 305.1. [α]_(D)=+24°, c=0.5, MeOH.

Step 4′ for Compound 8a: Synthesis of(+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)-phenyl)-piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]-pyrimidin-2(3H)-onewas prepared according to the same procedure described for Compound 7,starting from(+)-1-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine.1H-NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 7.50 (m, 1H), 7.27-6.97 (m,3H), 6.83 (m, 1H), 6.73-6.74 (m, 1H), 4.36-4.45 (m, 2H), 4.08 (m, 2H),3.25-3.38 (m, 2H), 3.00-3.06 (m, 2H), 2.94 (s, 3H), 2.63-2.71 (m, 2H),and 2.53-2.58 (m, 6H). [α]_(D)=+24°, c=0.1, AcOH. Absolutestereochemistry of the chiral center is unknown.

Steps 3″ and 4″ for Compound 8b:(−)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onewas prepared according to the same procedure described for Compound 7,starting from(−)-4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)-piperazine-1-carboxylate(3) leading by a step 3″ to the(−)-1-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine. LCMS(ESI positive ion) m/z: calculated: 604.65; Observed; 605.2 (M+1); HPLCpurity (XB0595TF): 98.81%; ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (brs, 1H),7.96 (s, 1H), 7.22-7.28 (m, 2H), 6.74-6.85 (m, 2H), 6.73-6.74 (m, 1H),4.36-4.45 (m, 2H), 4.09 (s, 2H), 3.28-3.30 (m, 1H), 3.23-3.26 (m, 1H),3.00-3.06 (m, 4H), 2.71-2.94 (m, 3H), and 2.64 (s, 6H). [α]_(D)=−39°,c=0.1, AcOH. Absolute stereochemistry of the chiral center is unknown.

Example 77:5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of tert-butyl4-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)-piperazine-1-carboxylate:In an open vial tert-butyl4-(2,4-difluoro-5-(2-(methylthio)ethoxy)phenyl)-piperazine-1-carboxylate(20 g, 51.48 mmol, prepared as described in Example 7, Step 1) and ureahydrogen peroxide (21.78 g, 231.68 mmol) were heated to 90° C. After 1hour the reaction mixture was allowed to room temperature. About 500 mLof ethyl acetate was added and stirred for 0.5 h, then filtered.Concentration of the filtrate afforded the crude product. It waspurified by column chromatography using 50% ethyl acetate in petroleumether to afford the product as off white solid (9 gram, 42%) LCMS (ESIpositive ion) m/z: 421.

Step 2: Synthesis of1-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazinehydrochloride (7): To an ice cold solution of tert-butyl4-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazine-1-carboxylate (9 g, 21.40 mmol) in dichloromethane (50 mL)was added a solution of HCl in in diethyl ether (50 mL). After stirringat 0° C. for 0.5 h, it was allowed to reach room temperature and stirredfor 16 h. The reaction mixture was concentrated under reduced pressureat room temperature. The residue obtained was triturated with diethylether to afford the pure product (10 g). LCMS (ESI positive ion) m/z:321 (M+1).

Step 3: To a stirred suspension of1-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazinehydrochloride (7 g, 22.13 mmol) in dry dichloroethane (70 mL), triethylamine (6.259 g, 61.97 mmol) and freshly prepared2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)-acetaldehyde(7 g, 22.13 mmol) were added. After stirring at room temperature for 3h, sodium triacetoxy borohydride (9.339 g, 44.26 mmol) was added. Theresulting mixture was stirred at room temperature for 24 h. Aftercompletion, the reaction mixture was diluted with dichloromethane. Theorganic layer separated was washed successively with saturatedbicarbonate solution and saturated brineution. Then it was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude obtained was purified by column chromatography (230-400 silicagel, 5% methanol/dichloromethane as an eluent) to afford the product asoff white solid (3.2 g, 26%). LCMS (ESI positive ion) m/z: 621 (M+1).¹H-NMR (400 MHz, DMSO-d6): δ 8.31 (s, 2H), 7.95 (d, J=0.92 Hz, 1H),7.23-7.29 (m, 2H), 6.82 (t, J=8.60 Hz, 1H), 6.73-6.74 (m, 1H), 4.40 (t,J=5.64 Hz, 2H), 4.08 (t, J=5.96 Hz, 2H), 3.62 (t, J=5.44 Hz, 2H), 3.07(s, 3H), 2.94 (s, 4H), 2.71 (t, J=6.04 Hz, 2H), and 2.67-2.68 (m, 4H),

Example 78:5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of tert-butyl4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (2): To a mixtureof 4-Bromo-3-fluorophenol (1, 10 g, 0.052 mol), tert-butylpiperazine-1-carboxylate (11.70 g, 0.063 mol), DavePhos (0.515 g, 0.001mol) and Pd₂(dba)₃ (0.958 g, 0.001 mol) was added LHMDS (115 mL of 1.0 Msolution in THF, 0.115 mol) at 0° C. under nitrogen. The reactionmixture was heated at 65° C. for 24 h and monitored by TLC. The crudereaction mixture was neutralized with saturated NH₄Cl and extracted withethyl acetate (2×100 mL). The combined organic layer was concentratedand purified by column chromatography to afford the title compound asoff white solid (2.25 g, 14.5%). LCMS (ESI positive ion) m/z:calculated: 296.15; observed: 297.2 (M+1).

Step 2: Synthesis of tert-butyl4-(2-fluoro-4-(2-(methylthio)ethoxy)phenyl)piperazine-1-carboxylate (3):To a mixture of tert-butyl4-(2-fluoro-4-(2-(methylthio)ethoxy)phenyl)piperazine-1-carboxylate (2,0.3 g, 1.102 mmol) and 1-chloro-2-methylsulfanyl-ethane (0.168 g, 1.519mmol) in N,N-Dimethylformamide (3 mL), was added potassium carbonate(0.419 g, 3.027 mmol) and the reaction mixture was heated at 90° C. for16 h. After the reaction completion (TLC), the reaction mixture wasdiluted with water (10 mL) and extracted with ethyl acetate. Combinedorganic layer was washed with saturated brine solution, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude obtained was purified by column chromatography (50% EtOAc/Hexaneas eluent) to afford the product as off white solid (0.3 g, 52.8%). LCMS(ESI positive ion) m/z: calculated: 370.48; observed: 370.9 (M+). ¹H-NMR(400 MHz, DMSO-d6): δ 7.02 (m, 1H), 6.85 (d, J=2.80 Hz, 1H), 6.72 (d,J=2.00 Hz, 1H), 4.09-4.12 (m, 2H), 3.45 (d, J=4.40 Hz, 4H), 2.80-2.86(m, 6H), 2.14 (s, 3H), and 1.42 (s, 9H).

Step 3: Synthesis of tert-butyl4-(2-fluoro-4-(2-(methylsulfonyl)ethoxy)phenyl)-piperazine-1-carboxylate(4): To a solution of tert-butyl4-[2-fluoro-4-(2-methylsulfanylethoxy)phenyl]piperazine-1-carboxylate(3, 0.5 g, 0.001 mmol) in 1,4-Dioxane (2 mL), Urea hydrogen peroxide(507.49 g, 0.005 mmol) was added. The mixture was heated to 85° C. for16 h. After the completion of the reaction, it was concentrated underreduced pressure. The residue was taken in ethyl acetate and filtered.The filtrate was washed with water, dried over Na₂SO₄ and concentratedunder reduced pressure. The crude product obtained was subjected tocolumn chromatography (1% Methanol in DCM solvent mixture as eluent) toafford the product tert-butyl4-(2-fluoro-4-(2-(methylsulfonyl)ethoxy)phenyl)piperazine-1-carboxylate(0.22 g, 40%).

LCMS (ESI positive ion) m/z: calculated: 402.48; observed: 403.3 (M+1).1H-NMR (400 MHz, DMSO-d6): δ 7.02 (broad s, 1H), 6.65-6.72 (m, 2H), 4.41(t, J=5.60 Hz, 2H), 3.64 (s, 4H), 3.44 (t, J=5.20 Hz, 2H), 3.07 (s, 3H),3.00 (s, 4H), and 1.50 (s, 9H).

Step 4: Synthesis of1-(2-fluoro-4-(2-(methylsulfonyl)ethoxy)phenyl)piperazine (5): To an icecold solution of tert-butyl4-[2-fluoro-4-(2-methylsulfonylethoxy)phenyl]piperazine-1-carboxylate(4, 0.22 g, 0.547 mmol) in dichloromethane (5 mL), 2M HCl in diethylether (2 mL) was added and the reaction mixture was stirred at 0° C. for1 h. After completion (TLC), the reaction mixture was concentrated underreduced pressure at room temperature. The residue obtained wastriturated with diethyl ether to afford the pure product. Then it wasdissolved in methanol, passed through Si-Carbonate resin for making freebase (0.105 g crude compound) directly used for the next step.

Step 5: Synthesis of5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfonyl)ethoxy)phenyl)-piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 78): To a mixture of1-[2-fluoro-4-(2-methylsulfinylethoxy)phenyl]piperazine (5, 105 mg,0.347 mmol) and 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methane sulfonate (125mg, 0.315 mmol) in N,N-Dimethylformamide (2 mL), was added DIPEA (204mg, 1.577 mmol) and the reaction mixture was stirred at 120° C. for 16h. After completion of the reaction (TLC & LCMS), the reaction mass wasconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with 5% Methanol in DCM to afford the product. Itwas further purified by RP preparative HPLC to afford the titlecompound. LCMS (ESI positive ion) m/z: calculated: 602.66; observed: 603(M+1). HPLC purity (PG_AM9010A3): 93.64%. 1H-NMR (400 MHz, DMSO-d6): δ8.31 (broad s, 2H), 7.95 (s, 1H), 7.24 (d, J=3.20 Hz, 1H), 6.87-6.98 (m,2H), 6.73-6.74 (m, 2H), 4.29 (t, J=5.60 Hz, 2H), 4.08 (t, J=5.60 Hz,2H), 3.58 (t, J=5.60 Hz, 2H), 3.05 (s, 3H), 2.86 (s, 4H), and 2.68-2.72(m, 6H).

Example 80:5-amino-3-(2-(4-(2-fluoro-4-(S-methylsulfonimidoyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of 1,2-difluoro-4-(methylsulfinyl)benzene (2): To anice cold solution of (3,4-difluorophenyl)(methyl)sulfane (1, 3.0 g,18.73 mmol) in DCM, was added 3-chloroperbenzoic acid (6.78 g, 39.33mmol) and stirred the reaction mixture at RT for 16 h. After thereaction completion (TLC), the reaction mixture was diluted with icecold water (30 mL) and the crude product was extracted with DCM. Organiclayer was successively washed with aqueous sodium thiosulphate, 10%NaHCO₃ brine solution, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product obtained waspurified by column chromatography (50% EtOAc/Hexane as eluent) to affordthe title product 2 as off white solid (2.8 g, 85%); LCMS (ESI positiveion) m/z: calculated: 176.18; Observed; 177.1 (M+1); 1H-NMR (400 MHz,DMSO-d6): δ 7.83-7.79 (m, 1H), 7.73-7.66 (m, 1H), 7.60-7.57 (m, 1H),2.78 (s, 1H).

Step 2: Synthesis of (3,4-difluorophenyl)(imino)(methyl)-16-sulfanone(3): To a solution of 1,2-difluoro-4-(methylsulfinyl)benzene (2, 2.8 g,15.89 mmol) in dichloromethane (60 mL) was added trifluoroacetamide(3.59 μg, 31.79 mmol), magnesium oxide (2.54 g, 63.57 mmol) and rhodiumdiacetate dimer (0.172 g, 0.429 mmol) and the reaction mixture waspurged with N₂ for 2 min. Iodobenzene diacetate (10.23 g, 31.79 mmol)was added and the reaction mixture was stirred at RT for 16 h. After thereaction completion (TLC), the reaction mixture was filtered throughcelite bed, concentrated and purified by preparative columnchromatography to afford the title compound 3 as off white solid (0.7 g,23.0%); LCMS (ESI positive ion) m/z: calculated: 191.20; Observed; 192.1(M+1); 1H-NMR (400 MHz, DMSO-d6): δ 8.07-8.02 (m, 1H), 7.86-7.83 (m,1H), 7.75-7.71 (m, 1H), 3.28 (s, 3H).

Step 3: Synthesis of(3-fluoro-4-(piperazin-1-yl)phenyl)(imino)(methyl)-16-sulfanone (4): Toa solution of (3,4-difluorophenyl)(imino)(methyl)-16-sulfanone (0.7 g,3.66 mmol) in N,N-Dimethylformamide (10 mL), was added Piperazine (0.32g, 3.66 mmol), Potassium carbonate (1.51 g, 10.98 mmol) and the reactionmixture was heated at 100° C. for 16 h. After the reaction completion(TLC), reaction mixture diluted with water and the crude product wasextracted with ethyl acetate, washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude obtained waspurified by preparative column chromatography to afford the desiredproduct 4 as off white solid. LCMS (ESI positive ion) m/z: calculated:257.33; Observed; 258.1 (M+1).

Step 4: Synthesis of5-amino-3-(2-(4-(2-fluoro-4-(S-methylsulfonimidoyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2 (3H)-one (Compound 80): A mixture of(3-fluoro-4-(piperazin-1-yl)phenyl) (imino)(methyl)-16-sulfanone (4,0.14 g, 0.545 mmol),2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4] triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (0.18 g, 0.45 mmol) and DIPEA(0.176 g, 1.36 mmol) in N,N-Dimethylformamide (2 mL), was stirred at120° C. for 16 h. After the reaction completion (TLC), reaction mixturediluted with water and the crude product was extracted with ethylacetate, washed with brine, dried over Na₂SO₄, filtered, concentratedand purified by preparative HPLC to afford the title compound as offwhite solid. LCMS (ESI positive ion) m/z: calculated: 557.62; Observed;558.1 (M+1). HPLC purity (XB_0595TF.M): 93.12%; 1H-NMR (400 MHz,DMSO-d6): δ 8.31 (brs, 2H), 7.95 (s, 1H), 7.61-7.57 (m, 2H), 7.24 (d,J=4.8 Hz, 1H), 7.15 (t, J=9.2 Hz, 1H), 6.73-6.72 (m, 1H), 4.14 (s, 1H),4.10 (t, J=6.00 Hz, 2H), 3.08 (m, 4H), 3.03 (s, 3H), 2.73 (t, J=6.00 Hz,2H), 2.67-2.65 (m, 4H).

Example 81:5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4-difluorobenzamide

Step 1: Synthesis of methyl 5-amino-2,4-difluorobenzoate (2): To an icecold solution of 5-amino-2,4-difluoro-benzoic acid (1.0 g, 0.017 mol) inmethanol (20.0 mL), thionyl chloride (2.514 mL, 0.035 mol) was added.The resulting mixture was heated at 80° C. for 1 h. Progress of thereaction was monitored by TLC. The reaction mixture was concentratedunder reduced pressure. DCM and water was added to the reaction mixture.Combined organic layer was dried over sodium sulphate, concentratedunder reduced pressure to afford the product methyl5-amino-2,4-difluoro-benzoate (2.8 g, 86.0%). LCMS (ESI positive ion)m/z: calculated: 187.15; Observed; 188.2 (M+1). 1H-NMR (400 MHz, CDCl3):δ 7.35-7.39 (m, 1H), 6.82-6.87 (m, 1H), and 3.92 (s, 3H).

Step 2: Synthesis of methyl 2,4-difluoro-5-(piperazin-1-yl)benzoate (3):A mixture of methyl 5-amino-2,4-difluoro-benzoate (2, 3.0 g, 0.016 mol)and 2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (3.719 g, 0.021mol) in diethylene glycol monomethyl ether (12 mL) was heated to 170° C.for 2.5 h. Progress of the reaction was monitored by TLC. Water wasadded to the reaction mixture and extracted with ethyl acetate. Theorganic part was discarded. Then pH of the aqueous part was adjustedwith sodium bicarbonate and extracted with ethyl acetate. Combinedorganic part was dried over anhydrous sodium sulphate, and concentratedunder reduced pressure. The crude product obtained was purified bycolumn chromatography to afford the product (1.5 g, 29.9%). LCMS (ESIpositive ion) m/z: calculated: 256.25; Observed; 257.0 (M+1).

Step 3: Synthesis of tert-butyl4-(2,4-difluoro-5-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (4):To an ice cold solution of methyl 2,4-difluoro-5-piperazin-1-yl-benzoate(3, 1.0 g, 0.009 mol) in DCM (10 mL), triethyl amine (1.510 mL, 0.012mol) and boc anhydride (1.278 mL, 0.006 mol) were added. The resultingmixture was stirred at room temperature for 16 h. Progress of thereaction was monitored by TLC. The reaction mixture was diluted withwater and extracted with ethyl acetate. The combined organic part waswashed with saturated brine solution, dried over anhydrous sodiumsulphate, concentrated under reduced pressure to afford the product(0.800 g, 58%). LCMS (ESI positive ion) m/z: calculated: 356.37;Observed; 357.2 (M+1).

Step 4: Synthesis of5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,4-difluorobenzoic acid (5):To a stirred solution of tert-butyl4-(2,4-difluoro-5-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (4,1.0 g, 0.003 mol) in THF: water (20 mL, 3:1), lithium hydroxide (0.176g, 0.004 mol) was added and reaction mixture was stirred at RT for 16 h.Progress of the reaction was monitored by TLC. The reaction mixture wasconcentrated to remove THF. 1.5N HCl was added to make the pH acidic.The solid formed was filtered to afford5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,4-difluorobenzoic acid(0.800 g, 97%). LCMS (ESI negative ion) m/z: calculated: 342.34;Observed; 341.0 (M−1).

Step 5: Synthesis of tert-butyl4-(5-((2-(dimethylamino)ethyl)carbamoyl)-2,4-difluorophenyl)piperazine-1-carboxylate(6): To a stirred solution of5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,4-difluorobenzoic acid (5,0.200 g, 0.0005 mol) in DCM (10 mL), N1,N1-dimethylethane-1,2-diamine(0.062 g, 0.0007 mol), DIPEA (0.306 mL, 0.002 mol) and T3P solution(0.438 mL, 0.001 mol) were successively added. The resulting mixture wasstirred at RT for 16 h. Progress of the reaction was monitored by TLC.Water was added to the reaction mixture and extracted withdichloromethane. Combined organic part was dried over anhydrous sodiumsulphate and concentrated under reduced pressure to afford the product(0.13 g, 46.4%). LCMS (ESI positive ion) m/z: calculated: 412.48;Observed; 413.6 (M+1).

Step 6: Synthesis ofN-(2-(dimethylamino)ethyl)-2,4-difluoro-5-(piperazin-1-yl)-benzamide(7): To an ice cold solution of tert-butyl4-(5-((2-(dimethylamino)ethyl)carbamoyl)-2,4-difluorophenyl)piperazine-1-carboxylate(6, 0.200 g, 0.0004 mol) in DCM (10 mL), HCl in diethyl ether solution(0.121 mL, 4M soln) was added. The resulting mixture was stirred at RTfor 16 h. Progress of the reaction was monitored by TLC. The reactionmixture was concentrated under reduced pressure. The residue wasneutralized with sodium bicarbonate and extracted with DCM. The organicpart was concentrated to affordN-(2-(dimethylamino)-ethyl)-2,4-difluoro-5-(piperazin-1-yl)benzamide(0.130 g, 62.28%). LCMS (ESI positive ion) m/z: calculated: 312.36;Observed; 313.2 (M+1).

Step 7: Synthesis of5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo-[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4-difluorobenzamide(Compound 81): To a stirred mixture of2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (8, 120 mg, 0.0003 mol) andN-[2-(dimethylamino)ethyl]-2,4-difluoro-5-piperazin-1-yl-benzamide (7,113 mg, 0.00036 mol) in DMF (5 mL), DIPEA (0.129 mL, 0.0009 mol) wasadded. The resulting mixture was heated to 120° C. for 16 h. After thecompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude residue obtained was purified by reversephase preparative HPLC purification to afford the product. LCMS (ESIpositive ion) m/z: calculated: 612.66; Observed; 613.2 (M+1). HPLCpurity (XB_0595TF): 92.76%. 1H-NMR (400 MHz, DMSO-d6): δ 7.72 (s, 1H),7.52-7.56 (m, 1H), 7.20 (s, 1H), 7.11-7.17 (m, 1H), 6.63 (t, J=2.00 Hz,1H), 4.31 (bs, 2H), 3.91 (t, J=7.84 Hz, 2H), 3.83 (m, 4H), 3.63 (t,J=6.12 Hz, 3H), 2.85 (m, 5H), and 2.56 (broad s, 6H).

Examples 83 and 84:5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-oneand5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of 4-amino-3-fluorophenol (2): To a stirred solutionof 3-fluoro-4-nitrophenol (1, 10 g, 0.064 mol) in ethyl acetate (140mL), Pd/C (4.0 g, 0.038 mol) was added under nitrogen atmosphere. Thereaction mixture was stirred under hydrogen bladder pressure for 16 h.The progress of the reaction was monitored by TLC. The reaction mixturewas filtered through Celite bed, and the filtrate was concentrated underreduced pressure to afford 4-amino-3-fluorophenol as light pink coloredsolid (6.9 g, 94%). LCMS (ESI positive ion); m/z: calculated: 127.12;Observed; 128.2 (M+1).

Step 2: Synthesis of 3-fluoro-4-(piperazin-1-yl)phenol hydrochloride(3): To a stirred solution of 4-amino-3-fluorophenol (2, 6.9 g, 0.054mol) in sulfolane (15 mL), bis(2-chloroethyl)amine hydrochloride (13.56g, 0.076 mol) was added. The reaction mixture was heated at 150° C. for16 h. After the completion of the reaction, the reaction mixture wascooled to RT. About 30 mL of cold acetone was added and stirred at 0° C.for 0.5 h. The solid formed was filtered, and dried to afford the3-fluoro-4-(piperazin-1-yl)phenol hydrochloride as black colored solid(10 g, 98%). LCMS (ESI positive ion); m/z: calculated: 196.23; Observed;197.1 (M+1).

Step 3: Synthesis of tert-butyl4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (4): To an ice coldstirred solution of 3-fluoro-4-(piperazin-1-yl)phenol hydrochloride (3,3.0 g, 0.015 mol) in DMF (30 mL), triethyl amine was added till itbecomes basic. Then BOC anhydride (3.0 mL, 0.041 mol) was added and thereaction was kept at 0° C. for 0.5 h. After the reaction completion itwas diluted with ethyl acetate and water. The organic layer was driedover anhydrous sodium sulphate and concentrated under reduced pressure.The crude product obtained was purified by column chromatography toafford tert-butyl 4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate(1.5 g, 86%). LCMS (ESI positive ion); m/z: calculated: 296.34;Observed; 297.1 (M+1).

Step 4: Synthesis of tert-butyl4-(2-fluoro-4-((4-hydroxytetrahydrofuran-3-yl)oxy)-phenyl)piperazine-1-carboxylate(5): To a stirred solution of tert-butyl4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (4, 1.5 g, 0.005mol) in dioxane (25 mL), 3,6-dioxabicyclo[3.1.0]hexane (1.089 g, 0.013mol) and cesium carbonate (2.47 g, 0.008 mol) were added. The reactionmixture was heated at 100° C. for 16 h. Progress of the reaction wasmonitored by TLC. Then reaction mixture was diluted with 10 mL of waterand extracted with ethyl acetate (10 mL×2). The combine organic layerwas dried over anhydrous MgSO₄, concentrated under reduced pressure toafford the tert-butyl4-(2-fluoro-4-((4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazine-1-carboxylateas brown colored solid (0.800 g, 98%). LCMS (ESI positive ion); m/z:calculated: 382.43; Observed; 383.1 (M+1).

Step 5: Synthesis of4-(3-fluoro-4-(piperazin-1-yl)phenoxy)tetrahydrofuran-3-ol (6): To anice cold solution of tert-butyl4-(2-fluoro-4-((4-hydroxytetrahydrofuran-3-yl)oxy)-phenyl)piperazine-1-carboxylate(5, 0.500 g, 0.001 mol) in dioxane (10 mL), HCl in dioxane solution (4Msolution, 1 mL) was added. After stirring for 16 h at room temperature,the reaction mixture was concentrated under reduced pressure. Theresidue was neutralized with 10% sodium bicarbonate solution andextracted with DCM. Concentration of the organic part afford4-(3-fluoro-4-(piperazin-1-yl)phenoxy)tetrahydrofuran-3-ol (0.250 g,88%). LCMS (ESI positive ion); m/z: calculated: 282.3; Observed; 283.2(M+).

Step 6: Synthesis of5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]-pyrimidin-2(3H)-one(Compound 83) and5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-hydroxy-tetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e]-[1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compounds 84): To a stirred solution of2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)-ethylmethane sulfonate (7, 0.320 g, 0.00080 mol) in DMF (8 mL),4-(3-fluoro-4-(piperazin-1-yl)phenoxy)tetrahydrofuran-3-ol (6, 0.273 μg,0.0009 mol) and N-ethyl-N-isopropylpropan-2-amine (0.218 mL, 0.002 mol)were added. The reaction mixture was heated at 120° C. for 16 h. Afterthe completion of the reaction, the reaction mixture was concentratedand the residue was purified by preparative HPLC purification. The pureproduct was then purified by chiral SFC purification to afford twoisomers5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(5.29 mg) and5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

First eluting enantiomer: LCMS (ESI positive ion); m/z: calculated:582.61; Observed; 583.2 (M+1). HPLC purity (XB_0595TF): 96.23%. 1H-NMR(400 MHz, DMSO-d6): δ 8.30 (bs, 2H), 7.95 (s, 1H), 7.23 (d, J=3.20 Hz,1H), 6.92-6.96 (m, 1H), 6.83-6.87 (m, 1H), 6.70-6.74 (m, 2H), 5.48 (bs,1H), 4.58 (d, J=4.00 Hz, 1H), 4.58 (d, J=4.00 Hz, 1H), 4.07 (t, J=6.40Hz, 2H), 3.99-4.03 (m, 1H), 3.85-3.89 (m, 1H), 3.71-3.74 (m, 1H),3.55-3.58 (m, 1H), 2.61 (s, 4H), 2.708 (m, 2H), and 2.67 (m, 4H).

Second-eluting enantiomer: LCMS (ESI positive ion); m/z: calculated:582.61; Observed; 583.2 (M+1). HPLC purity (XB_0595TF): 93.44%. 1H-NMR(400 MHz, DMSO-d6): δ 8.31 (bs, 2H), 7.96 (s, 1H), 7.24 (d, J=3.32 Hz,1H), 6.94 (t, J=9.36 Hz, 1H), 6.83-6.87 (m, 1H), 6.70-6.74 (m, 2H), 5.46(d, J=3.84 Hz, 1H), 4.58 (d, J=3.40 Hz, 1H), 4.16 (s, 1H), 4.08 (t,J=6.24 Hz, 2H), 4.02-4.03 (m, 1H), 3.86-3.89 (m, 1H), 3.72 (d, J=9.96Hz, 1H), 3.57 (d, J=9.60 Hz, 1H), 2.9277 (m, 4H), 2.9363 (m, 2H), and2.7029 (s, 4H).

Example 88:5-amino-3-(2-(4-(2-fluoro-5-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of(2-(3-bromo-4-fluorophenoxy)ethoxy)(tert-butyl)dimethylsilane (2): Amixture of 3-bromo-4-fluorophenol (1, 2.3 g, 0.012 mol),(2-bromoethoxy)(tert-butyl)dimethylsilane (3.74 g, 0.016 mol) in DMF (30mL), K2CO3 (2.49 g, 0.018 mol) was heated to 70° C. for 16 h. Progressof the reaction was monitored by TLC. After the reaction completion,water (20 mL) was added to the reaction mixture and extracted withdichloromethane (30 mL×2). The combined organic part was washed withsaturated brine solution, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford the title compound (2 g,29%), which was used as such for the next step.

Step 2: Synthesis of1-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-fluorophenyl)-piperazine(3): To a stirred solution of2-(3-bromo-4-fluoro-phenoxy)ethoxy-tert-butyl-dimethyl-silane (2, 1.0 g,0.003 mol) and piperazine (499 mg, 0.006 mol)) in toluene (15 mL),NaOBu-t (412 mg) was added. The resulting mixture was degassed withnitrogen. Then BINAP (107 mg, 0.00017 mol), and palladium acetate (262mg, 0.0003 mol) were added and the resulting mixture was heated to 110°C. for 16 h. After the completion, the reaction mixture was filtered,and filtrate was concentrated under reduced pressure. The crude residueobtained was purified by column chromatography to afford the titlecompound (0.3 g, 29.5%). LCMS (ESI positive ion) m/z: calculated:354.54; observed: 355.3 (M+1).

Step 3: Synthesis of 2-(4-fluoro-3-(piperazin-1-yl)phenoxy)ethan-1-ol(4): To an ice cold solution of1-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-fluorophenyl)-piperazine(3, 0.354 g, 0.0009 mol) in THF (10 mL), TBAF (0.499 mL, 4 M in THF) wasadded slowly. The resulting mixture was allowed to reach RT and stirredthere for 16 h. After reaction completion, the reaction mixture wasdiluted with water and ethyl acetate. The organic layer separated wasdried over anhydrous sodium sulphate, concentrated under reducedpressure. The crude product obtained was purified by columnchromatography to afford the title compound (0.240 g, 98.99%). LCMS (ESIpositive ion) m/z: calculated: 240.28; observed: 241.2 (M+1).

Step 4: Synthesis of5-amino-3-(2-(4-(2-fluoro-5-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 88): To a stirred solution of2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (0.300 g, 0.0007 mol) in DMF (8 mL),2-(4-fluoro-3-(piperazin-1-yl)phenoxy)ethan-1-ol (4, 0.218 g, 0.0009mol) and DIPEA (0.397 mL, 0.002 mol) were added. The reaction mixturewas heated to 120° C. for 16 h. After the completion, the reactionmixture was concentrated and the crude product obtained was purified byreverse phase preparative HPLC purification to afford the title compoundas off white solid. HPLC purity (XB_0595TF): 98.29%; LCMS (ESI positiveion) m/z: calculated: 540.57; observed: 541.0 (M+1). 1H-NMR (400 MHz,DMSO-d6): δ 9.19 (s, 1H), 8.39-8.45 (bs, 2H), 7.97 (s, 1H), 7.11 (m,1H), 6.75 (s, 1H), 6.59 (m, 2H), 4.86 (m, 1H), 4.32 (m, 2H), 3.95-3.98(m, 4H), 3.68-3.70 (m, 2H), 3.63 (m, 3H), 2.94-3.00 (m, 2H), and 3.69(s, 2H).

Example 90:5-amino-3-(2-(4-(2,4-difluoro-5-(morpholin-3-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of tert-butyl3-((5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2,4-difluorophenoxy)methyl)morpholine-4-carboxylate(2): To a stirred solution of benzyl4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (1, 1.2 g, 2.9mmol) and tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (1.1 g,4.3 mmol) in toluene (10 mL) was added triphenyl phosphine (1.8 g, 6.9mol) followed by the drop-wise addition of DIAD (1.39 g, 6.9 mmol) at 0°C. Reaction mixture was stirred at 110° C. for 16 h. After the reactioncompletion (TLC), the reaction mixture was diluted with water (20 mL)and extracted with ethyl acetate. Organic layer was washed withsaturated brine solution, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude obtained was purified bycolumn chromatography (20% EtOAc/Hexane) to afford the title compound asbrown liquid (1.4 g, 63.8%); LCMS (ESI positive ion) m/z: calculated:547.25; observed: 548.1 (M+1).

Step 2: Synthesis of tert-butyl3-((2,4-difluoro-5-(piperazin-1-yl)phenoxy)methyl)morpholine-4-carboxylate (3): To stirred solution of tert-butyl3-((5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2,4-difluorophenoxy)methyl)morpholine-4-carboxylate(0.5 g, 0.91 mmol) in EtOAc (20 mL) was added 10% Pd/C (0.2 g) undernitrogen atmosphere. The reaction mixture was stirred underhydrogenation atmosphere at room temperature for 16 h. The reactionprogress was monitored by TLC. After completion, the reaction mixturewas filtered using celite to remove the Pd/C. The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto afford the title compound as brown gummy solid (280 mg, 73.5%); LCMS(ESI positive ion) m/z: calculated: 413.21; observed: 414.3 (M+1).

Step 3: Synthesis of tert-butyl3-((5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-methyl)morpholine-4-carboxylate (4): To a stirred solution of tert-butyl3-((2,4-difluoro-5-(piperazin-1-yl)phenoxy)methyl)-morpholine-4-carboxylate(3, 100 mg, 0.242 μmmol) and2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (86 mg, 0.218 mmol) in N,N-dimethylformamide (10 mL)in 50 mL sealed tube was added DIPEA (94 mg, 0.726 mmol) and thereaction mixture was stirred at 120° C. for 16 h. After completion ofthe reaction (TLC & LCMS), the solvent was removed under reducedpressure. The reaction mass was treated with water and extracted withethyl acetate. Organic layer was washed with saturated brine solution,dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude product was purified by preparative TLC to affordthe title compound as dark brown solid (25 mg, 14.4%); LCMS (ESIpositive ion) m/z: calculated: 713.26; observed: 714.1 (M+1).

Step 4: Synthesis of5-amino-3-(2-(4-(2,4-difluoro-5-(morpholin-3-ylmethoxy)-phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 90): To a stirred solution of tert-butyl3-((3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-4,5-difluorophenoxy)-methyl)-morpholine-4-carboxylate(4, 25 mg, 0.035 mmol) in DCM (5 mL) at 0° C., 4 N HCl in dioxane (1.5mL) was added and the reaction mixture was stirred at RT for 5 h. Afterthe completion of reaction (TLC), the reaction mixture was concentratedunder reduced pressure to get the crude product, which was washed withacetonitrile to afford title compound as brown solid (16 mg, 73.3%);HPLC purity (AM9010A3): 98.49%; LCMS (ESI positive ion) m/z: calculated:613.20; observed: 614.1 (M+1); ¹H-NMR (400 MHz, DMSO-d6): δ 10.33 (brs,1H), 9.53 (brs, 2H), 8.41 (brs, 2H), 7.97 (s, 1H), 7.40 (t, J=11.20 Hz,1H), 7.26 (d, J=3.20 Hz, 1H), 7.01 (t, J=7.60 Hz, 1H), 6.75-6.74 (m,1H), 4.33-4.23 (m, 4H), 4.02-3.93 (m, 4H), 3.69-3.62 (m, 6H), 3.27 (m,3H), 2.98 (m, 4H).

Example 91:5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of benzyl4-(5-((1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)oxy)-2,4-difluorophenyl)piperazine-1-carboxylate(2): To a suspension of benzyl4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (6.0 g, 17.22mmol) and tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.82g, 20.67 mmol) in dry DMF (30 mL), was added K₂CO₃ (7.13 g, 51.67 mmol)and the reaction mixture was heated at 100° C. for 16 h. Aftercompletion of reaction (TLC), the reaction mixture was concentratedunder reduced pressure and the crude was purified by columnchromatography to afford the title compound 2 as color less liquid (3.5g, 36%); LCMS (ESI positive ion); m/z: calculated: 533.57; Observed:534.1 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 7.38-7.28 (m, 6H), 6.89-6.88(m, 1H), 5.49-5.48 (m, 1H), 5.10-4.65 (m, 2H), 4.15 (m, 1H), 4.05-4.03(m, 1H), 3.59-3.49 (m, 6H), 2.96-2.88 (m, 4H), 1.40 (s, 9H).

Step 2: Synthesis of benzyl4-(5-(((3S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2,4-difluorophenyl)piperazine-1-carboxylate(3): A solution of benzyl4-(5-((1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)oxy)-2,4-difluorophenyl)piperazine-1-carboxylate (3.5 g, 6.56 mmol) in dichloromethane (60 mL)was cooled to −70° C. and DAST (2.11 g, 0.013 mmol) was added slowly,and the reaction mixture was stirred at RT for 16 h. After the reactioncompletion (TLC) the reaction mixture was diluted with water and thecrude product was extracted with dichloromethane. The organic layer wassuccessively washed with 10% NaHCO₃, water, brine, dried over Na₂SO₄,filtered and concentrated to afford the crude product. The diastereomersformed were separated by normal silica column chromatography as peak 1and peak 2. The enantiomers present in the peak 1 were separated throughSFC chiral column; Method: YMC cellulose SC_IPA; 70:30 (A: B), A=liquidCO₂, B=IPA, flow rate: 0.9 mL/min; wave length: 220 nm. The first peakeluted out of chiral column was concentrated to afford the titlecompound 3 as off white solid (0.7 g, 19%); LCMS (ESI positive ion);m/z: calculated: 535.56; Observed; 536.2 (M+1); 1H-NMR (400 MHz,DMSO-d6): δ 7.38-7.29 (m, 6H), 6.97-6.95 (m, 1H), 5.38-5.25 (m, 1H),5.11-5.04 (m, 2H), 3.84-3.79 (m, 7H), 3.22-3.16 (m, 4H), 1.42 (s, 9H).

Step 3: Synthesis of tert-butyl (3S,4S)-3-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)-4-fluoropyrrolidine-1-carboxylate(4): A suspension of benzyl4-(5-(((3S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2,4-difluorophenyl)piperazine-1-carboxylate(0.23 g, 0.429 mmol) in ethyl acetate (10 mL) was charged with 10%Palladium on carbon (0.049 g) and stirred under hydrogen bladderpressure for 5 h at room temperature. After completion of reaction(TLC), the reaction mass was filtered through pad of celite andconcentrated to afford the title compound 4 as pale brown solid (0.16 g,92.8%); LCMS (ESI positive ion); m/z: calculated: 401.43; Observed;402.2 (M+1); ¹H-NMR (400 MHz, CD₃OD): δ 6.92 (t, J=8.8 Hz, 1H),6.56-6.51 (m, 2H), 3.57 (m, 4H), 2.91 (t, J=4.80 Hz, 4H), 1.49 (s, 9H).

Step 4: Synthesis of tert-butyl(3R,4R)-3-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-4-fluoropyrrolidine-1-carboxylate(5): To a solution of tert-butyl (3S,4S)-3-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)-4-fluoropyrrolidine-1-carboxylate(0.16 g, 0.399 mmol) and2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methane sulfonate (0.15 g, 0.39 mmol) in dryDMF (3 mL), was added N,N-Di isopropyl ethylamine (0.13 g, 0.83 mmol)and the reaction mixture was heated in a sealed tube at 120° C. for 16h. After completion of reaction (LCMS), the reaction mixture wasconcentrated under reduced pressure and purified by preparatory HPLC toafford the title compound 5 as off white solid (0.06 g, 21.4%). LCMS(ESI positive ion); m/z: calculated: 701.73; Observed; 702.3 (M+1);1H-NMR (400 MHz, DMSO-d6): δ 8.30 (s, 2H), 7.95 (t, J=0.80 Hz, 1H),7.30-7.23 (m, 2H), 6.88 (t, J=8 Hz, 1H), 6.73-6.72 (m, 1H), 5.32 (s,1H), 5.06-5.04 (m, 1H), 4.06 (t, J=12 Hz, 2H), 3.60-3.49 (m, 4H), 2.92(s, 4H), 2.73-2.68 (m, 2H), 2.67-2.51 (m, 4H), 1.41 (s, 9H).

Step 5: Synthesis of5-amino-3-(2-(4-(2,4-difluoro-5-(((3R,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 91): To an ice cooled solution of tert-butyl(3R,4R)-3-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-4-fluoropyrrolidine-1-carboxylate(0.06 g, 0.086 mmol) in dichloromethane (3 mL), was added 2M HCl indiethyl ether (3 mL) under nitrogen pressure. The reaction mixture wasstirred at RT for 3 h. After completion of reaction, the reactionmixture was concentrated under reduced pressure, triturated with diethylether and dried to afford title compound 91 as off white solid (0.02 g,38.9%). LCMS (ESI positive ion); m/z: calculated: 601.61; Observed;602.2 (M+1); HPLC purity (XB_0595TF): 97.51%; 1H-NMR (400 MHz, DMSO-d6):10.26 (brs, 1H), 9.83 (brs, 2H), 8.41 (brs, 2H), 7.96 (d, J=0.30 Hz,1H), 7.46-7.43 (m, 1H), 7.40-7.26 (m, 1H), 7.25-7.08 (m, 1H), 6.75-6.74(m, 1H), 5.42 (s, 1H), 5.26-5.24 (m, 1H), 4.33 (m, 2H), 3.94-3.91 (m,2H), 3.64-3.55 (m, 10H), 3.39-3.27 (m, 2H), 3.17-3.05 (m, 2H).

Example 95:(S)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of (R)-2-oxopyrrolidin-3-yl methanesulfonate (6): To astirred solution of (3R)-3-hydroxypyrrolidin-2-one (5, 1.0 g, 9.9 mmol)in DCM (15 mL) was added TEA (2.0 g, 19.8 mmol) and mesyl chloride (1.36g, 11.9 mmol) at 0° C.

Resulting reaction mixture was stirred at RT for 2 h. After completionof the reaction, reaction mixture was quenched with NH₄Cl solution andextracted with DCM. Organic layer was washed with saturated brinesolution, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude was purified by column chromatography to getpure product (1.2 g, 67.0%); ¹H-NMR (400 MHz, CDCl₃): δ 5.17 (t, J=7.96Hz, 1H), 3.53-3.50 (m, 1H), 3.43-3.38 (m, 1H), 3.27 (s, 3H), 2.69-2.64(m, 1H), 2.43-2.36 (m, 1H).

Step 2: Synthesis of tert-butyl(S)-4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazine-1-carboxylate (2): To a stirred solution of tert-butyl4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (1, 900 mg,2.86 mmol) in DMF (20 mL) was added K₂CO₃ (791 mg, 5.73 mmol) and(R)-2-oxopyrrolidin-3-yl methanesulfonate (6, 769 mg, 4.3 mmol) andheated at 80° C. for 16 h. After completion of the reaction, thereaction mixture was treated with saturated NH₄Cl solution and extractedwith ethyl acetate. Organic layer was washed with saturated brinesolution, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude reaction mixture was purified by columnchromatography to afford the title compound (900 mg, 78%); LCMS (ESIpositive ion) m/z: calculated: 397.18; observed: 398.1 (M+1).

Step 3: Synthesis of(S)-3-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)pyrrolidin-2-one (3): To astirred solution of tert-butyl(S)-4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazine-1-carboxylate (2, 900 mg, 2.26 mmol) in dichloromethane (20mL) at 0° C., 4 N HCl in dioxane (2.5 mL) was added dropwise and stirredat RT for 3 h. After the reaction completion (TLC), the reaction mixturewas concentrated under reduced pressure. The salt was dissolved inmethanol and neutralized using tosic acid scavenger resin to get thefree base as the off white gum (400 mg, 58.2%); LCMS (ESI positive ion)m/z: calculated: 297.13; observed: 298.1 (M+1).

Step 4: Synthesis of(S)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)-phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyri-midin-2(3H)-one(Compound 95): To a stirred solution of(S)-3-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)pyrrolidin-2-one (3, 350mg, 1.18 mmol) in DMF (10 mL) was added DIPEA (608 mg, 4.71 mmol) and2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (420 mg, 1.06 mmol). The reaction mixture was stirred at 120°C. for 16 h. After completion of reaction (TLC & LCMS), the solvent wasremoved under reduced pressure and the reaction mixture was partitionedbetween water and ethyl acetate. The separated organic layer was washedwith brine solution, dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrate under reduced pressure and purified by flashcolumn chromatography using (3% methanol/dichloromethane) to afford thetitle compound (250 mg, 34.1%); HPLC purity (XB0595TF): 96.08%; LCMS(ESI positive ion) m/z: calculated: 597.17; observed: 598.0 (M+1);¹H-NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 8.08 (s, 1H), 7.95 (s, 1H),7.24-7.18 (m, 2H), 6.97 (t, J=8.80 Hz, 1H), 6.74-6.73 (m, 1H), 4.92 (t,J=7.60 Hz, 1H), 4.08 (t, J=6.00 Hz, 2H), 3.27-3.18 (m, 2H), 2.91 (m,4H), 2.73-2.64 (m, 6H), 2.03-1.98 (m, 1H).

Example 96:(R)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of (S)-2-oxopyrrolidin-3-yl methanesulfonate (6): To asolution of (S)-3-hydroxypyrrolidin-2-one (5, 2.0 g, 0.02 mol) in DCM(10 mL) was added triethylamine (4.0 g, 0.04 mol) and mesyl chloride(2.49 g, 0.022 mol) at 0° C. Resulting reaction mixture was stirred atRT for 2 h. After completion of the reaction, reaction mixture wasquenched with NH₄Cl solution and extracted with DCM. Organic layer waswashed with saturated brine solution, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to afford(S)-2-oxopyrrolidin-3-yl methanesulfonate as pale yellow liquid (1.4 g,39.5%); LCMS (ESI positive ion) m/z: calculated: 179.03; observed: 180.1(M+1).

Step 2: Synthesis of tert-butyl(R)-4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazine-1-carboxylate (2): To a solution of tert-butyl4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (1, 1.5 g, 4.8mmol) in DMF (20 mL) was added (S)-2-oxopyrrolidin-3-yl methanesulfonate(6, 1.3 g, 7.2 mmol) and K₂CO3 (1.32 g, 9.6 mmol) and heated to 90° C.for 16 h. After completion of the reaction, the reaction mixture wastreated with saturated NH₄Cl solution and extracted with ethyl acetate.Organic layer was washed with saturated brine solution, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude reaction mixture was purified by column chromatography to affordthe title compound as pale brown solid (1.0 g 45.8%); LCMS (ESI positiveion) m/z: calculated: 397.18; observed: 398.1 (M+1).

Step 3: Synthesis of(R)-3-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)pyrrolidin-2-one (3): To astirred solution of tert-butyl4-[2,4-difluoro-5-[(3R)-2-oxopyrrolidin-3-yl]oxy)phenyl]piperazine-1-carboxylate (2, 1.0 g, 2.5 mmol) in dichloromethane (15 mL)at 0° C., 4 N HCl in dioxane (10 mL) was added dropwise and stirred atRT for 2 h.

After the reaction completion (TLC), the reaction mixture wasconcentrated under reduced pressure. The salt was dissolved in methanoland neutralized using Tosic acid scavenger resin to get the free base asthe off white gum (600 mg 72.9%); LCMS (ESI positive ion) m/z:calculated: 297.13; observed: 298.2 (M+1).

Step 4: Synthesis of(R)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)-phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 96): To a solution of2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (300 mg, 0.76 mmol) in DMF (10 mL) was added DIPEA(0.49 g, 3.79 mmol) and(R)-3-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)pyrrolidin-2-one (337 mg,1.14 mmol). The reaction mixture was stirred at 120° C. for 16 h. Aftercompletion of reaction (TLC & LCMS), the solvent was removed underreduced pressure and the reaction mixture was partitioned between waterand ethyl acetate. The separated organic layer was washed with brinesolution, dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrate under reduced pressure and purified by flash columnchromatography using (3% methanol/dichloromethane) to afford the titlecompound. HPLC purity (XB0595TF): 97.73%; LCMS (ESI positive ion) m/z:calculated: 597.17; observed: 598.0 (M+1); ¹H-NMR (400 MHz, DMSO-d6): δ8.32 (brs, 2H), 8.09 (s, 1H), 7.95 (s, 1H), 7.19-7.25 (m, 2H), 6.97 (t,J=8.64 Hz, 1H), 6.74 (s, 1H), 4.93 (t, J=7.56 Hz, 2H), 4.08 (t, J=6.00Hz, 2H), 3.18-3.26 (m, 2H), 2.91 (m, 4H), 2.64-2.73 (m, 6H), 1.98-2.03(m, 1H).

Example 99:5-amino-3-(2-(4-(2-fluoro-4-(morpholin-3-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of tert-butyl3-((4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-3-fluorophenoxy)methyl)morpholine-4-carboxylate(2): To a stirred solution of benzyl4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (1, 2.0 g, 6.05mmol) in toluene (20 mL) was added tert-butyl3-(hydroxymethyl)morpholine-4-carboxylate (2.63 g, 12.1 mmol), triphenylphosphine (4.76 g, 12.1 mmol) and DIAD (2.45 g, 12.1 mmol) at RT. Thereaction mixture was stirred at 120° C. in seal tube for 16 h. Reactionprogress was monitored by TLC. After completion of the reaction,reaction mixture was partitioned between water and ethyl acetate andseparated organic layer was washed with brine solution dried overanhydrous Na₂SO₄, and concentrated under vacuum to afford as a crudeproduct. The crude obtained was purified by column chromatography (20%EtOAc/Hexane) to afford tert-butyl tert-butyl3-((4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-3-fluorophenoxy)-methyl)morpholine-4-carboxylate(1.0 g, 31.2%); LCMS (ESI positive ion) m/z: calculated: 529.26;observed: 530.1 (M+1).

Step 2: Synthesis of tert-butyl3-((3-fluoro-4-(piperazin-1-yl)phenoxy)methyl)-morpholine-4-carboxylate(3): To a stirred solution of tert-butyl3-((4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-3-fluorophenoxy)methyl)morpholine-4-carboxylate(2, 600 mg, 1.1 mmol) in ethyl acetate (10 mL) was added 10% Pd/C (120mg) at RT and stirred under hydrogen atmosphere for 16 h. Aftercompletion, the reaction mixture was filtered using celite to remove thePd/C. The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford tert-butyl3-((3-fluoro-4-(piperazin-1-yl)phenoxy)methyl)morpholine-4-carboxylateas gummy solid (350 mg, 61.7%); LCMS (ESI positive ion) m/z: calculated:395.22; observed: 396.1 (M+1).

Step 3: Synthesis of tert-butyl3-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e]-[1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-methyl)-morpholine-4-carboxylate(4): To a stirred solution of2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (200 mg, 0.631 mmol) and tert-butyl tert-butyl3-((3-fluoro-4-(piperazin-1-yl)phenoxy)methyl)morpholine-4-carboxylate(300 mg, 0.756 mmol) in DMF (10 mL) was added DIPEA (292 mg, 2.27 mmol)and the reaction mixture was stirred at 100° C. for 16 h. Reactionprogress was monitored by TLC, the reaction mixture was partitionedbetween water and ethyl acetate. The separated organic layer was washedwith NaHCO₃ solution, brine solution, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford crude product. The crudeproduct was purified by preparative HPLC to get pure tert-butyl3-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]-triazolo[1,5-c]pyrimidin-3(2H)yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)methyl)morpholine-4-carboxylate(80 mg, 21.4%); LCMS (ESI positive ion) m/z: calculated: 695.26;observed: 696.1 (M+1).

Step 4: Synthesis of5-amino-3-(2-(4-(2-fluoro-4-(morpholin-3-ylmethoxy)phenyl)-piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 99): To a stirred solution of tert-butyl3-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e]-[1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)methyl)morpholine-4-carboxylate (4, 80 mg, 0.11 mmol) in DCM (5 mL) was added 2N HCl in diethyl ether (2 mL) and the resulting reaction mixture wasstirred at RT for 2 h. After completion of the reaction, reactionmixture was concentrated under reduced pressure to get crude compoundand it was purified by preparative HPLC to get pure5-amino-3-(2-(4-(2-fluoro-4-(morpholin-3-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-oneas off white solid (15 mg, 22%); HPLC purity (XB0595TF): 95.90%; LCMS(ESI positive ion) m/z: calculated: 595.21; observed: 596.1 (M+1);¹H-NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (m, 1H), 7.24 (dd,J=0.80 Hz and 3.40 Hz, 1H), 6.92 (t, J=10.00 Hz, 1H), 6.80 (dd, J=2.80Hz and 14.00 Hz, 1H), 6.73 (dd, J=2.00 Hz and 3.40 Hz, 1H), 6.67 (dd,J=2.40 Hz and 8.80 Hz, 1H), 4.08 (t, J=6.40 Hz, 2H), 3.81-3.74 (m, 3H),3.67-3.64 (m, 1H), 3.34 (m, 1H), 3.18 (t, J=10.80 Hz, 1H), 3.01-2.98 (m,1H), 2.85 (m, 4H), 2.77-2.67 (m, 4H), 2.63 (m, 4H).

Example 100:5-amino-3-(2-(4-(2-fluoro-4-(morpholin-2-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of tert-butyl2-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate (2): To a cooledsuspension of tert-butyl 2-(hydroxymethyl) morpholine-4-carboxylate (1,5.0 g, 23.01 mmol) in dry DCM (50 mL) was added methane sulfonylchloride drop wise (3.42 g, 29.92 mmol) and the reaction mixture wasstirred at RT for 16 h. After the completion of reaction the reaction(TLC), the reaction mixture was diluted with water and the crude productwas extracted with DCM, concentrated and purified by columnchromatography (30% EtOAc/Hexane as eluent) to afford the title compound2 as light yellow gum (6.0 g, 87%). LCMS (ESI positive ion) m/z:calculated: 295.35; Observed; 196.1 (M+1-100).

Step 2: Synthesis of tert-butyl2-((4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-3-fluorophenoxy)methyl)morpholine-4-carboxylate(3): To a suspension of benzyl 4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (2, 0.5 g, 1.51 mmol) and tert-butyl2-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate (0.53 g, 1.81mmol) in dry DMF (10 mL) was added K₂CO₃ (0.63 g, 4.54 mmol) and thereaction mixture was heated at 100° C. for 16 h. After the completion ofreaction the reaction (TLC), reaction mass was filtered through pad ofcelite and the filtrate was concentrated and purified by columnchromatography (30% EtOAc/Hexane as eluent) to afford the title compound3 as off white solid (0.35 g, 39%); LCMS (ESI positive ion) m/z:calculated: 529.61; observed: 530.3 (M+1). 1H-NMR (400 MHz, DMSO-d6): δ7.39-7.35 (m, 5H), 7.32-7.00 (m, 1H), 6.97-6.85 (m, 1H), 6.84-6.72 (m,1H), 5.11 (s, 2H), 3.98-3.96 (m, 2H), 3.86-3.73 (m, 2H), 3.70-3.66 (m,2H), 3.64-3.43 (m, 2H), 3.38-3.34 (m, 4H), 3.32 (m, 1H), 2.89 (m, 4H),

Step 3: Synthesis of tert-butyl2-((3-fluoro-4-(piperazin-1-yl)phenoxy)methyl) morpholine-4-carboxylate(4): A solution of tert-butyl2-((4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-3-fluorophenoxy)methyl)morpholine-4-carboxylate (3, 0.33 g, 0.62 mmol) in ethyl acetate (6 mL)was charged with 10% Palladium on Carbon (0.060 g) and the reactionmixture was stirred under hydrogen bladder pressure at room temperaturefor 16 h. After the reaction completion (TLC) the reaction mixture wasfiltered through pad of celite and the filtrate was concentrated underreduced pressure to afford tert-butyl the title compound 4 as lightbrown solid (0.18 g, 65%); LCMS (ESI positive ion) m/z: calculated:395.48; observed: 396.3 (M+1). 1H-NMR (400 MHz, DMSO-d6): δ 6.95 (t,J=10.00 Hz, 1H), 6.84-6.80 (m, 1H), 6.72-6.70 (m, 1H), 3.96-3.95 (m,2H), 3.92-3.83 (m, 2H), 3.74-3.67 (m, 2H), 3.65-3.64 (m, 1H), 3.33-2.99(m, 9H), 1.42 (s, 9H).

Step 4: Synthesis of tert-butyl2-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-methyl)-orpholine-4-carboxylate(5): A mixture of2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (0.16 μg, 0.40 μmmol), tert-butyl2-((3-fluoro-4-(piperazin-1-yl)phenoxy)methyl) morpholine-4-carboxylate(4, 0.176 g, 0.444 mmol) and DIPEA (0.26 g, 2.01 mmol) in dry DMF (3 mL)was heated at 120° C. for 16 h in a sealed tube.

After completion (TLC), the reaction mixture was cooled to RT, dilutedwith water and the crude solid was filtered and purified by columnchromatography (70% EtOAc/Hexane as eluent) to afford the title compound5 as off white solid (0.05 g, 16.4%); LCMS (ESI positive ion) m/z:calculated: 695.77; observed: 696.0 (M+1). 1H-NMR (400 MHz, DMSO-d6): δ8.30 (brs, 2H), 7.95 (brs, 1H), 7.24 (s, 1H), 6.92 (m, 1H), 6.83-6.73(m, 1H), 6.69 (d, J=8.80 Hz, 2H), 4.08-3.95 (m, 2H), 3.85-3.83 (m, 2H),3.70 (m, 2H), 3.43 (m, 2H), 3.33 (m, 1H), 2.85 (m, 4H), 2.68-2.63 (m,4H), 2.45-2.33 (m, 4H), 1.41 (s, 9H).

Step 5: Synthesis of5-amino-3-(2-(4-(2-fluoro-4-(morpholin-2-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 100): To an ice cold solution of tert-butyl2-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)methyl) morpholine-4-carboxylate (5,0.04 g, 0.057 mmol) in dichloromethane (1 mL) was added 2 M HCl inDiethylether (1 mL) and the reaction mixture was stirred at RT for 2 h.After completion of the reaction (TLC), the solid formed (HCl salt) wasfiltered, dried under reduced pressure to afford the title compound 100as off white solid (0.014 g, 36%); HPLC purity (XB_0595TF.M): 95.72%;LCMS (ESI positive ion) m/z: calculated: 595.35; observed: 596.2 (M+1);1H-NMR (400 MHz, DMSO-d6): δ 10.11 (brs, 1H), 9.39-9.41 (m, 2H), 8.42(brs, 2H), 7.97 (s, 1H), 7.26-7.27 (m, 1H), 7.04 (t, J=9.64 Hz, 1H),6.90-6.94 (m, 1H), 6.74-6.77 (m, 2H), 4.14 (t, J=3.32 Hz, 2H), 3.99-4.03(m, 4H), 3.91-3.94 (m, 2H), 3.78 (t, J=12.12 Hz, 1H), 3.60-3.61 (m, 2H),3.30-3.48 (m, 3H), 3.271-3.198 (m, 2H), 3.17-3.00 (m, 4H).

Examples 101 and 102:5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-oneand5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of benzyl4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (2): To an ice coldstirred solution of 4-bromo-3-fluorophenol (1, 15 g, 0.079 mol), benzylpiperazine-1-carboxylate (20.76 g, 0.094 mol), DavePhos (3.704 g, 0.009mol), Pd₂(dba)₃ (7.186 g, 0.008 mol) in THF (100 mL), LHMDS (100 mL) wasadded. After addition, the reaction was allowed to reach roomtemperature. Then it was heated to 65° C. for 24 h. After thecompletion, the reaction mixture was quenched with saturated ammoniumchloride solution and extracted with ethyl acetate. Combined organiclayer was washed with saturated brine solution, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudeobtained was purified by column chromatography (230-400 silica gel (30%EA/Pet ether as an eluent) to afford the product as off white solid(10.00 g, 30.1%). LCMS (ESI positive ion) m/z: calculated: 330.36;observed: 331.1 (M+1).

Step 2: Synthesis of benzyl4-(4-((1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2-fluorophenyl)piperazine-1-carboxylate(3): To a stirred solution of benzyl4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (6.8 g, 20.58mmol), tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (4.986g, 26.76 mmol) in 1,4-dioxane (20 mL), Cs2CO3 (10.3 g, 30.88 mmol) wasadded. The resulting mixture was stirred at 100° C. for 16 h. Then itwas filtered to remove the inorganic. The crude residue obtained onconcentration of the filtrate was purified by column chromatography(230-400 silica gel (30% EA/Pet ether as an eluent) to afford anoff-white solid (6.00 g, 56.0%). LCMS (ESI positive ion) m/z:calculated: 515.58; observed: 516.2 (M+1).

Step 3: Synthesis of benzyl4-(4-((−1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2-fluorophenyl)piperazine-1-carboxylate(4A & 4B): To an ice cold stirred solution of benzyl4-(4-((1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)oxy)-2-fluorophenyl)piperazine-1-carboxylate(3, 6 g, 11.64 mmol) in DCM (30 mL), DAST (5.816 g, 34.91 mmol) wasadded to the reaction mixture at −20° C. The resulting mixture wasstirred at −20° C. for 0.5 h and then RT for 16 h. After the completionof reaction, the reaction mixture quenched with saturated NaHCO₃solution and extracted with DCM. Combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude obtained was purified by column chromatography (230-400 silica gel(30% EA/hexane as an eluent) to afford two fractions of product.Fraction-1-1.4 g, Fraction-2-900 mg. LCMS (ESI positive ion) m/z:calculated: 517.57; observed: 518.2 (M+1).

The two fractions were further purified by chiral SFC purification (0.5%DEA in IPA, YMC Cellulose-SC) to afford enantiomers 4A and 4B

Step 4: Synthesis of tert-butyl(3R,4R)-3-fluoro-4-(3-fluoro-4-(piperazin-1-yl)phenoxy)-pyrrolidine-1-carboxylate(5A): To a stirred solution of benzyl4-(4-(((3R,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2-fluorophenyl)piperazine-1-carboxylate(4A, 430 mg, 0.831 mmol), in ethyl acetate (10 mL), Pd/C 10% (200 mg)was added under nitrogen atmosphere. The resulting mixture was stirredat RT under hydrogen atmosphere for 32 h. Then it was filtered throughcelite pad to remove the Pd/C. The crude residue obtained onconcentration of the filtrate to afford as sticky material. The crudematerial was taken next step without purification (0.23 g, 69.3%). LCMS(ESI positive ion) m/z: calculated: 383.44; observed: 384.3 (M+1).

Step 5: Synthesis of tert-butyl(3R,4R)-3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo-[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-4-fluoropyrrolidine-1-carboxylate(7A): To a stirred solution of tert-butyl(3R,4R)-3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo-[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-4-fluoropyrrolidine-1-carboxylate(5A, 100 mg, 0.261 mmol) in DCM (10 mL),2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)acetaldehyde(82 mg, 0.261 mmol), and Et₃N (52 mg, 0.552 mmol) were added. Theresulting mixture was stirred at room temperature for 3 h. ThenNaBH(OAc)₃ (165 mg 0.522 mmol) was added and the resulting mixture wasstirred at room temperature for 24 h. After completion, the reactionmixture was diluted with DCM. The organic part separated was washedsuccessively with saturated bicarbonate solution, saturated brinesolution. After drying over anhydrous Na₂SO₄, it was filtered andconcentrated under reduced pressure. The crude obtained was purified bycolumn chromatography (230-400 silica gel (5% MeOH/DCM as an eluent) toafford the product as off white solid (0.025 g, 14.0%). LCMS (ESIpositive ion) m/z: calculated: 683.74; observed: 684.3 (M+1).

Step 6: Synthesis of5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 101): To an ice cold stirred solution of tert-butyl(3R,4R)-3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-4-fluoropyrrolidine-1-carboxylate(7A, 25 mg, 0.037 mmol) in DCM (1 mL), HCl in ether (0.073 mL) wasadded. The resulting mixture was stirred at 0° C. for 1 h. After thecompletion of reaction, the reaction mixture was concentrated underreduced pressure. The crude product obtained was triturated with etherto afford product as off white solid (0.013 g, 52.75%). LCMS (ESIpositive ion) m/z: calculated: 583.62; observed: 584.0 (M+1). HPLCpurity (XB0595TF): 92.31%. 1H-NMR (400 MHz, DMSO-d6): δ 9.86 (broad s,1H), 9.69 (broad s, 1H), 9.47 (broad s, 1H), 8.42 (m, 2H), 7.97 (s, 1H),7.26 (d, J=3.60 Hz, 1H), 7.06-7.10 (m, 2H), 6.87 (d, J=8.40 Hz, 1H),6.74-6.76 (m, 1H), 5.49 (m, 1H), 5.07-5.13 (m, 1H), 4.32 (brs, 2H),3.72-3.92 (m, 2H) 3.62 (d, J=5.20 Hz, 2H), 3.39 (t, J=5.20 Hz, 5H), and3.02 (brs, 5H).

Step 4: Synthesis of tert-butyl(3S,4S)-3-fluoro-4-(3-fluoro-4-(piperazin-1-yl)phenoxy)-pyrrolidine-1-carboxylate(5B): To a stirred solution of benzyl4-(4-(((3S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2-fluorophenyl)piperazine-1-carboxylate(4B, 380 mg, 0.734 mmol), in ethyl acetate (10 mL), Pd/C 10% (200 mg)was added under nitrogen atmosphere. The resulting mixture was stirredat RT under hydrogen atmosphere for 32 h. Then it was filtered throughcelite pad to remove the Pd/C. The crude residue obtained onconcentration of the filtrate to afford as sticky material. The crudematerial was taken next step without purification (0.2 g, 71.04%). LCMS(ESI positive ion) m/z: calculated: 383.44; observed: 384.3 (M+1).

Step 5: Synthesis of tert-butyl(3S,4S)-3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo-[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-4-fluoropyrrolidine-1-carboxylate(7B): To a stirred solution of tert-butyl(3S,4S)-3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo-[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-phenoxy)-4-fluoropyrrolidine-1-carboxylate(5B, 70 mg, 0.187 mmol) in DCM (10 mL),2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)-acetaldehyde(57 mg, 0.187 mmol), and Et₃N (52 mg, 0.548 mmol) were added. Theresulting mixture was stirred at room temperature for 3 h. ThenNaBH(OAc)₃ (77 mg, 0.365 mmol) was added and the resulting mixture wasstirred at room temperature for 24 h. After completion, the reactionmixture was diluted with DCM. The organic part separated was washedsuccessively with saturated bicarbonate solution, saturated brinesolution. After drying over anhydrous Na₂SO₄, it was filtered andconcentrated under reduced pressure. The crude obtained was purified bycolumn chromatography (230-400 silica gel (5% MeOH/DCM as an eluent) toafford the product as off white solid (0.027 g, 19.9%). LCMS (ESIpositive ion) m/z: calculated: 683.74; observed: 684.3 (M+1).

Step 6: Synthesis of5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)-phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 102): To an ice cold stirred solution of tert-butyl(3S,4S)-3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-phenoxy)-4-fluoropyrrolidine-1-carboxylate(7B, 25 mg, 0.037 mmol) in DCM (1 mL), HCl in ether (0.073 mL) wasadded. The resulting mixture was stirred at 0° C. for 1 h. After thecompletion of reaction, the reaction mixture was concentrated underreduced pressure. The crude product obtained was triturated with etherto afford product as off white solid (0.017 g, 69.7%). LCMS (ESIpositive ion) m/z: calculated: 583.62; observed: 584.4 (M+1). HPLCpurity (XB_0595TF): 93.18%. 1H-NMR (400 MHz, DMSO-d6): δ 10.27 (broad s,1H), 9.69-9.82 (m, 2H), 8.41 (broad s, 2H), 7.97 (m, 1H), 7.26-7.27 (m,1H), 7.05-7.10 (m, 2H), 6.87-6.90 (m, 1H), 6.75 (t, J=1.60 Hz, 1H), 5.49(d, J=4.00 Hz, 1H), 5.07-5.13 (m, 1H), 4.32 (d, J=5.20 Hz, 2H),3.73-3.93 (m, 2H), 3.49-3.66 (m, 2H), 3.40-3.44 (m, 3H), 3.30-3.39 (m,2H), 3.25-3.30 (m, 3H), and 3.07-3.10 (m, 2H).

Example 111:5-amino-3-(2-(4-(2,4-difluoro-5-(((1s,4s)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of tetrahydro-2H-thiopyran-4-yl methane sulfonate (2):To an ice cold solution of tetrahydro-2H-thiopyran-4-ol (2.0 g, 16.94mmol) and triethyl amine (4.26 g, 42.2 mmol) in dichloromethane (30 mL)was added wise, methane sulfonyl chloride (2.1 g, 18.62 mmol) and thereaction mixture was stirred at RT for 12 h. After the reactioncompletion the reaction mixture was diluted with water and the crudeproduct was extracted with dichloromethane. The organic layer was dried,concentrated and purified by column chromatography (20% EtOAc/Hexane aseluent) to afford the title compound 2 as light brown liquid (3.1 g,94%). The crude was directly taken for the next step as such.

Step 2: Synthesis of tert-butyl4-(2,4-difluoro-5-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-1-carboxylate(3): To a solution of tetrahydro-2H-thiopyran-4-yl methanesulfonate (2,2.25 g, 11.45 mmol) and tert-butyl4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (3 μg, 9.55μmmol) in N,N-dimethylformamide (10 mL), was added K₂CO₃ (2.69 g, 19.04mmol) and the reaction mixture was heated at 100° C. for 16 h. After thereaction completion (TLC), the reaction mixture was diluted with water(30 mL) and extracted with ethyl acetate. Organic layer was washed withbrine solution, water, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford crude product, which wasfurther purified by column chromatography (20% EtOAc/Hexane as eluent)to afford the title compound 3 as off white solid (1.7 g, 42.54%); LCMS(ESI positive ion) m/z: calculated: 414.51; observed: 415.1 (M+1).

Step 3: Synthesis of tert-butyl4-(2,4-difluoro-5-((1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-1-carboxylate(4): A solution of tert-butyl4-(2,4-difluoro-5-(tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-1-carboxylate (3, 1.7 g, 4.101 mmol) in acetic acid (20 mL),was cooled to 0° C., H₂O₂ (30%, 2 mL) was added and the reaction mixturewas stirred at the same temperature for 1 h. After the reactioncompletion (TLC), reaction mixture was neutralized with cooled 10% NaOHsolution and the crude product was extracted with dichloromethane. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to afford racemicproduct as off white solid. Yield: (1.62 g, 91.8%). The isomers presentin the racemic mixture were separated through SFC chiral method. Thefirst peak eluted out (peak 1) was concentrated to afford the titlecompound 4 as off white solid (0.65 g, 80%); LCMS (ESI positive ion)m/z: calculated: 430.51; observed: 431.1 (M+1). 1H-NMR (400 MHz,DMSO-d6): 7.31 (t, J=12 Hz, 1H), 6.97-6.93 (s, J=8.8 Hz 1H), 4.43-4.40(m, 1H), 3.46-3.16 (m, 4H), 2.96-2.90 (m, 6H), 2.75-2.67 (m, 2H),2.50-2.30 (m, 2H), 1.86-1.83 (m, 2H), 1.42 (s, 9H).

Step 4: Synthesis of (is,4s)-4-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)tetrahydro-2H-thiopyran1-oxide (5): To an ice cold solution of tert-butyl4-(2,4-difluoro-5-(((1s,4s)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-1-carboxylate(4, 0.48 g, 1.11 mmol) in dichloromethane (10 mL), was addedtrifluoroacetic acid (1.3 mL) and the reaction mixture was stirred at RTfor 5 h. After the reaction completion (TLC), excess TFA was removed byevaporation and the reaction mixture was neutralized by tosic acid resintreatment to afford the title compound 5 as off white solid (0.31 g,84%); LCMS (ESI positive ion) m/z: calculated: 330.39; observed: 331.0(M+1).

Step 5: Synthesis of 5-amino-3-(2-(4-(2,4-difluoro-5-(((1s,4s)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]-triazolo[1,5-c]pyrimidin-2(3H)-one (Compound 111): A mixture of2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (0.35 g, 0.88 mmol),(1s,4s)-4-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)tetrahydro-2H-thiopyran1-oxide (5, 0.32 g, 0.97 mmol) and DIPEA (0.34 g, 2.64 mmol) in dry DMF(3 mL) was heated at 120° C. for 16 h in a sealed tube. After thecompletion (TLC), the reaction mixture was cooled to RT, diluted withwater and the crude solid was filtered and purified by columnchromatography (70% EtOAc/Hexane as eluent) to afford the title compound111 as off white solid. LCMS (ESI positive ion) m/z: calculated: 630.39;observed: 631.1 (M+1); HPLC purity (XB_0595TF.M): 96.25%.

¹H-NMR (400 MHz, DMSO-d6): δ 8.29 (s, 2H), 7.94 (s, 1H), 7.23 (t,J=10.72 Hz, 2H), 6.80 (t, J=8.52 Hz, 1H), 6.72 (t, J=1.72 Hz, 1H), 4.36(t, J=9.08 Hz, 1H), 4.05 (t, J=7.32 Hz, 2H), 2.90 (s, 6H), 2.79 (d,J=11.56 Hz, 2H), 2.73 (d, J=8.80 Hz, 2H), 2.69 (t, J=9.92 Hz, 4H), 2.14(q, J=10.68 Hz, 2H), 1.97 (d, J=12.84 Hz, 2H).

Example 112:5-amino-3-(2-(4-(2,4-difluoro-5-(((1r,4r)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of (1r,4r)-4-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)tetrahydro-2H-thiopyran1-oxide (2): To an ice cold solution of tert-butyl4-(2,4-difluoro-5-(((1r,4r)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-1-carboxylate(1, 0.3 g, 0.697 mmol) in dichloromethane (10 mL), was addedtrifluoroacetic acid (1.3 mL) and the reaction mixture was stirred at RTfor 5 h. After the reaction completion (TLC), excess TFA was removed byevaporation and the reaction mixture was neutralized by tosic acid resintreatment to afford the title compound 2 as off white solid (0.20 g,85%); LCMS (ESI positive ion) m/z: calculated: 330.39; observed: 331.0(M+1).

Step 2: Synthesis of5-amino-3-(2-(4-(2,4-difluoro-5-(((1r,4r)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]-triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 112): A mixture of2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (0.23 g, 0.58 mmol),(1r,4r)-4-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)tetrahydro-2H-thiopyran1-oxide (2, 0.21 g, 0.63 mmol) and DIPEA (0.23 g, 1.74 mmol) in dry DMF(2.5 mL) was heated at 120° C. for 16 h in a sealed tube. After thecompletion (TLC), the reaction mixture was cooled to RT, diluted withwater and the crude solid was filtered and purified by columnchromatography (70% EtOAc/Hexane as eluent) to afford the title compound3 as off white solid. LCMS (ESI positive ion) m/z: calculated: 630.39;observed: 631.1 (M+1); HPLC purity (XB_0595TF.M): 94.36%. ¹H-NMR (400MHz, DMSO-d6): δ 8.29 (s, 2H), 7.94 (s, 1H), 7.23 (t, J=11.8 Hz, 2H),6.85 (t, J=8.64 Hz, 1H), 6.72 (t, J=1.72 Hz, 1H), 4.57 (s, 1H), 4.05 (t,J=7.32 Hz, 2H), 2.93 (brs, 6H), 2.72-2.67 (m, 4H), 2.62 (s, 6H),2.34-2.32 (m, 2H), 1.85 (d, J=12.84 Hz, 2H).

Examples 119 and 120:(R)-5-amino-3-(2-(4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-oneand(S)-5-amino-3-(2-(4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of (3,4-difluorophenyl)(methyl)sulfane (2): To astirred solution of 3,4-difluorobenzenethiol (1, 8.0 g, 54.74 mmol) inDMF (25 mL) was added K₂CO₃ (9.08 g, 65.68 mmol) followed by Mel (8.5 g,60.21 mmol) at 0° C. in sealed tube and stirred at RT for 16 h. Aftercompletion (TLC), the reaction mass was poured into ice cold water andextracted with diethyl ether. Organic layer was washed with saturatedbrine solution, dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give the title compound. The crude productthat was used for next step without purification (8.05 g, 88.1%).

Step 2: Synthesis of 1,2-difluoro-4-(methylsulfinyl)benzene (3): To astirred solution of (3,4-difluorophenyl)(methyl)sulfane (2, 8.0 g, 49.94mmol) in DCM (120 mL) was added mCPBA (8.6 g, 49.94 mmol) at 0° C. andstirred at RT for 16 h. After completion (TLC), the reaction mass wasquenched with saturated sodium bicarbonate solution and extracted withDCM. Organic layer was washed with saturated brine solution, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude obtained was purified by column chromatography to give the titlecompound (5.0 g, 55.6%); LCMS (ESI positive ion) m/z: calculated:176.01; observed: 177.0 (M+1).

Step 3: Synthesis of tert-butyl4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine-1-carboxylate (4, 5): Toa stirred solution of tert-butyl piperazine-1-carboxylate (5.3 g, 28.38mmol) in DMF (50 mL) at 0° C. was added K₂CO₃ (7.8 g, 56.76 mmol)followed by 1,2-difluoro-4-(methylsulfinyl)-benzene (3, 5.0 g, 28.38mmol). The reaction mixture was stirred at 145° C. for 16 h. Aftercompletion (TLC), the reaction mass was quenched with water andextracted with ethyl acetate. Organic layer was washed with saturatedbrine solution, dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude obtained was purified by columnchromatography to give the title compound (2.2 g, 22.7%); LCMS (ESIpositive ion) m/z: calculated: 342.14; Observed; 343.0 (M+1).

Racemic mixture (0.22 g) was subjected to chiral separation by SFC (0.22g sample was dissolved in 3 mL of methanol), column—Lux A1 mobile phase:70:30 (A: B), A=liquid CO₂, B=methanol, flow rate: 3.0 mL/min; wavelength: 220 nm) to yield 810 mg of peak 1 (4) and 820 mg of peak 2 (5)respectively.

Note: Peak 1 from SFC purification was arbitrarily considered as (S)isomer and peak 2 was considered as (R) isomer.

Step 4: Synthesis of (S)-1-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine(6): To a stirred solution of tert-butyl(S)-4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine-1-carboxylate (4,800 mg, 0.292 mmol) in DCM (18 mL) was added TFA (1.3 g, 11.68 mmol) at0° C. The reaction mixture was stirred at RT for 3 h. After the reactioncompletion (TLC), the reaction mixture was concentrated under reducedpressure. The salt was dissolved in methanol and neutralized using Tosicacid scavenger resin to get the title compound as free base (510 mg,88.2%); LCMS (ESI positive ion) m/z: calculated: 242.09; observed: 243.1(M+1).

Step 5: Synthesis of(S)-5-amino-3-(2-(4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 120): To a stirred solution of(S)-1-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine (6, 200 mg, 0.825mmol) in DMF (10 mL) was added DIPEA (426.7 mg, 3.302 mmol) followed by2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (294 mg, 0.743 mmol) in sealed tube and stirred at120° C. for 16 h.

After completion (TLC & LCMS), the solvent was removed under reducedpressure.

The reaction mass was quenched with water and extracted with ethylacetate. Organic layer was washed with saturated brine solution, driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The crude obtained was purified by column chromatography to get thetitle compound (180 mg, 37.7%); HPLC purity (XB0595TF): 94.08%; LCMS(ESI positive ion) m/z: calculated: 542.13; observed: 543.2 (M+1);¹H-NMR (400 MHz, DMSO-d6): δ 8.30 (brs, 2H), 7.95 (m, 1H), 7.48-7.39 (m,2H), 7.24 (d, J=3.60 Hz, 1H), 7.15 (t, J=8.40 Hz, 1H), 6.74-6.73 (m,1H), 4.09 (m, 2H), 3.04 (m, 4H), 2.72 (s, 3H), 2.67 (m, 4H).

Example 119:(S)-5-amino-3-(2-(4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of (R)-1-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine(7) To a stirred solution of tert-butyl(R)-4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine-1-carboxylate (5,800 mg, 0.292 mmol) in DCM (18 mL) was added TFA (1.3 g, 11.68 mmol) at0° C. The reaction mixture was stirred at RT for 3 h. After the reactioncompletion (TLC), the reaction mixture was concentrated under reducedpressure. The salt was dissolved in methanol and neutralized using Tosicacid scavenger resin to get the title compound as free base (510 mg,88.8%); LCMS (ESI positive ion) m/z: calculated: 242.09; observed: 243.1(M+1).

Step 2: Synthesis of(R)-5-amino-3-(2-(4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 119): To a stirred solution of(R)-1-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine (7, 200 mg, 0.825mmol) in DMF (10 mL) was added DIPEA (426.7 mg, 3.302 mmol) followed by2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (294 mg, 0.743 mmol) in sealed tube and stirred at120° C. for 16 h. After completion (TLC & LCMS), the solvent was removedunder reduced pressure. The reaction mass was treated with water andextracted with ethyl acetate. Organic layer was washed with saturatedbrine solution, dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude obtained was purified by columnchromatography to get the title compound (120 mg, 25.1%); HPLC purity(XB0595TF): 93.75%; LCMS (ESI positive ion) m/z: calculated: 542.13;observed: 541.0 (M−1); ¹H-NMR (400 MHz, DMSO-d6): δ 8.32 (brs, 2H), 7.96(s, 1H), 7.49-7.40 (m, 2H), 7.25 (d, J=3.16 Hz, 1H), 7.16 (t, J=8.52 Hz,1H), 6.74-6.73 (m, 1H), 4.09 (m, 2H), 3.04 (m, 4H), 2.76-2.66 (m, 9H).

Examples 121 and 122:5-amino-3-(2-(4-(2-fluoro-4-(((1s,4s)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-oneand5-amino-3-(2-(4-(2-fluoro-4-(((1r,4r)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of tetrahydro-2H-thiopyran-4-ol (11): To an ice coldsolution of tetrahydrothiopyran-4-one (10, 5 g, 0.043 mol) in methanol(40 mL), 5N sodium hydroxide solution (10 mL) solution was added slowly.Then sodium borohydride (0.488 g, 0.013 mol) was added portion wise.After addition, the reaction mixture was allowed to reach roomtemperature. After the reaction completion (˜1 h), the reaction mixturewas poured in to water and extracted with dichloromethane. Combinedorganic layer was washed with saturated brine solution, dried overanhydrous Na₂SO₄, and concentrated under reduced pressure. The crudeproduct was purified by column chromatography using 5% methanol in DCMto afford the pure product (4 g, 51.90%). 1H-NMR (400 MHz, DMSO-d6): δ4.69 (d, J=4.24 Hz, 1H), 3.41-3.47 (m, 1H), 2.65-2.70 (m, 2H), 2.50-2.54(m, 1H), 2.47 (d, J=2.76 Hz, 1H), 2.00-2.02 (m, 2H), and 1.96-1.99 (m,2H).

Step 2: Synthesis of tetrahydro-2H-thiopyran-4-yl methanesulfonate (12):To an ice cold solution of tetrahydrothiopyran-4-ol (11, 3.5 g, 0.030mol) in dichloromethane (40 mL), triethyl amine (5.982 g, 0.059 mol) andmethane sulfonyl chloride (0.727 g, 0.006 mol) were added. After 3 h,the reaction mixture poured into water and extracted withdichloromethane. Combined organic layer was washed with saturated brinesolution, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The crude residue was subjected to column chromatography using2% methanol in DCM as eluent to afford the product (6 g, 98.07%).

Step 3: Synthesis of tert-butyl4-(2-fluoro-4-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)-piperazine-1-carboxylate(2): To a solution of tert-butyl4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (1, 1.6 g,5.399 mmol) and tetrahydrothiopyran-4-yl methane sulfonate (12, 1.272 g,6.479 mmol) in DMF (20 mL), was added K2CO3 (1.490 g, 10.80 mmol). Theresulting mixture was heated to 100° C. for 16 h. After the reactioncompletion (TLC), the reaction mixture was diluted with water andextracted with ethyl acetate. Combined organic layer was washed withsaturated brine solution, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude obtained was purified bycolumn chromatography (50% EtOAc/Hexane as eluent) to afford the productas off white solid (1.5 g, 69%). LCMS (ESI positive ion) m/z:calculated: 396.52; Observed; 397.1 (M+1).

Step 4: Synthesis of tert-butyl4-(2-fluoro-4-((1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-1-carboxylate(3, 4): To an ice cold mixture oftert-butyl4-(2-fluoro-4-tetrahydrothiopyran-4-yloxy-phenyl)-piperazine-1-carboxylate(1.650 μg, 4.161 mmol, 1 eq) in acetic acid (25 mL), hydrogen peroxide(1 mL) was added drop wise and stirred at same temperature for 1 h.After the reaction completion (TLC), the reaction mixture poured in to4N sodium hydroxide solution (20 mL) and extracted with ethyl acetate.Combined organic layer was washed with saturated brine solution, driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The crude obtained was purified by column chromatography (80%EtOAc/Hexane as eluent) to afford the product as off white solid (1.4 g,80.7%). LCMS (ESI positive ion) m/z: calculated: 412.52; Observed; 413.2(M+1).

The racemic mixture (1.4 g) was subjected to chiral separation by SFC(1.4 g sample was dissolved in 10 mL of methanol), column—YMC Amylose-SAmobile phase: 70:30 (A: B), A=liquid CO2, B=0.5% DEA in Methanol flowrate: 3 mL/min; wave length: 210 nm. Yield 600 mg of peak 1 (3) and 500mg of peak 2 (4).

Step 5: Synthesis of(1s,4s)-4-(3-fluoro-4-(piperazin-1-yl)phenoxy)tetrahydro-2H-thiopyran1-oxide (5): To an ice cold solution of tert-butyl4-(2-fluoro-4-(((1s,4s)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)-piperazine-1-carboxylate(3, 0.5 g, 1.212 mmol) in dichloromethane (10 mL), trifluoro acetic acid(0.207 g, 0.002 mol). After stirring at 0° C. for 1 h, the reactionmixture was concentrated under reduced pressure at ambient temperature.The residue obtained was triturated with diethyl ether. Then it wasdissolved in methanol, passed through Si-Carbonate resin to afford thefree base which was used directly for the next step (0.38 g, 99.35%).1H-NMR (400 MHz, DMSO-d6): δ 7.02 (d, J=9.20 Hz, 1H), 6.90-6.98 (m, 1H),6.76-6.79 (m, 1H), 4.40-4.43 (m, 1H), 3.18 (s, 1H), 3.05 (t, J=2.40 Hz,4H), 2.93-2.99 (m, 4H), 2.85 (t, J=11.20 Hz, 1H), 2.79 (d, J=2.40 Hz,2H), 2.12 (t, J=10.00 Hz, 2H), and 1.96 (d, J=12.40 Hz, 2H).

Step 6: Synthesis of5-amino-3-(2-(4-(2-fluoro-4-(((1s,4s)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]-triazolo-[1,5-c]pyrimidin-2(3H)-one(Compound 121): To a mixture of2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (7, 0.385 g, 0.971 mmol) and(1s,4s)-4-(3-fluoro-4-(piperazin-1-yl)phenoxy)tetrahydro-2H-thiopyran1-oxide (0.334 g, 1.068 mmol) in DMF (4 mL), DIPEA (0.626 g, 4.856 mmol)was added. The reaction mixture was stirred at 90° C. for 16 h. Aftercompletion, the reaction mixture was diluted with water (10 mL) andextracted with ethyl acetate. Combined organic layer was washed withsaturated brine solution, dried over anhydrous Na₂SO₄, filtered,concentrated. The crude product was purified by reverse phasepreparative HPLC to afford the product as off white solid (0.045 g,7.5%). LCMS (ESI positive ion) m/z: calculated: 612.70; Observed; 613(M+1). HPLC purity (XB_0595TF): 99.21%. 1H-NMR (400 MHz, DMSO-d6): δ8.31 (broad s, 2H), 7.95 (s, 1H), 7.24 (d, J=3.20 Hz, 1H), 6.88-6.93 (m,2H), 6.73-6.77 (m, 2H), 4.59 (s, 1H), 4.08 (t, J=5.60 Hz, 2H), 3.50 (d,J=12.80 Hz, 2H), 2.86-2.95 (m, 6H), 2.63-2.71 (m, 6H), 2.27-2.33 (m, 2H)and 1.80-1.83 (m, 2H).

Example 122:5-amino-3-(2-(4-(2-fluoro-4-(((1r,4r)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 5: Synthesis of(1r,4r)-4-(3-fluoro-4-(piperazin-1-yl)phenoxy)tetrahydro-2H-thiopyran1-oxide (6): To an ice cold solution of tert-butyl4-(2-fluoro-4-(((1r,4r)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-1-carboxylate(4, 0.5 μg, 1.212 mmol) in dichloromethane (10 mL), trifluoro aceticacid (0.207 g, 0.002 mol). After stirring at 0° C. for 1 h, the reactionmixture was concentrated under reduced pressure at ambient temperature.The residue obtained was triturated with diethyl ether. Then it wasdissolved in methanol, passed through Si-Carbonate resin to afford thefree base which was used directly for the next step (0.375 g, 98.05%).1H-NMR (400 MHz, DMSO-d6): δ 7.02 (d, J=9.20 Hz, 1H), 6.90-6.98 (m, 1H),6.76-6.79 (m, 1H), 4.40-4.43 (m, 1H), 3.18 (s, 1H), 3.05 (t, J=2.40 Hz,4H), 2.93-2.99 (m, 4H), 2.85 (t, J=11.20 Hz, 1H), 2.79 (d, J=2.40 Hz,2H), 2.12 (t, J=10.00 Hz, 2H), and 1.96 (d, J=12.40 Hz, 2H).

Step 6: Synthesis of5-amino-3-(2-(4-(2-fluoro-4-(((1r,4r)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]-triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 122): To a mixture of2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (7, 0.235 g, 0.593 mmol) and(1s,4s)-4-(3-fluoro-4-(piperazin-1-yl)phenoxy)tetrahydro-2H-thiopyran1-oxide (0.204 g, 0.652 mmol) in DMF (2 mL), DIPEA (0.382 g, 2.964 mmol)was added. The reaction mixture was stirred at 90° C. for 16 h. Aftercompletion, the reaction mixture was diluted with water (10 mL) andextracted with ethyl acetate. Combined organic layer was washed withsaturated brine solution, dried over anhydrous Na₂SO₄, filtered,concentrated. The crude product was purified by reverse phasepreparative HPLC to afford the product as off white solid (0.031 g,8.4%). LCMS (ESI positive ion) m/z: calculated: 612.70; Observed; 613.1(M+1). HPLC purity (XB_0595TF): 98.46%. 1H-NMR (400 MHz, DMSO-d6): δ8.31 (broad s, 2H), 7.95 (s, 1H), 7.24 (d, J=3.20 Hz, 1H), 6.88-6.93 (m,2H), 6.73-6.77 (m, 2H), 4.39 (t, J=9.20 Hz, 1H), 4.08 (t, J=6.00 Hz,2H), 3.50 (d, J=12.40 Hz, 2H), 2.72-2.95 (m, 6H), 2.63-2.70 (m, 6H),2.13-2.33 (m, 2H) and 1.85-1.99 (m, 2H).

Example 126:5-amino-3-(2-(4-(2-fluoro-4-(1-oxidothiomorpholino)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of 4-bromo-2-fluoroaniline (2): To a stirred solutionof 4-bromo-2-fluoro-1-nitrobenzene (1, 9.0 g, 13.64 mmol) and aceticacid (11.5 g, 0.57 mol) in ethanol (60 mL) was added iron powder (15.9g, 0.285 mol). The reaction mixture was stirred at 80° C. for 1 h. Aftercompletion of the reaction, reaction mixture was diluted with EtOAc andfiltered through celite bed. The filtrate was concentrated under reducedpressure to get the crude compound and it was used for the next stepdirectly (6.0 g, 76.5%); LCMS (ESI positive ion) m/z: calculated:188.96; observed: 192.0 (M+1).

Step 2: Synthesis of 1-(4-bromo-2-fluorophenyl)piperazine (3): To astirred solution of 4-bromo-2-fluoroaniline (2, 6.0 g, 31.58 mmol) indiglyme (4.8 mL) was added bis(2-chloroethyl)amine hydrogen chloride(6.7 g, 37.89 mmol) and the reaction mixture was stirred at 160° C. for16 h. After completion of the reaction (TLC), reaction mixture wascooled to RT and was treated with cold acetone. The precipitated solidwas filtered and used for the next step directly (5.0 g, 61%); LCMS (ESIpositive ion) m/z: calculated: 258.02; observed: 259.0 (M+1).

Step 3: Synthesis of tert-butyl4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate (4): To a stirredsolution of 1-(4-bromo-2-fluorophenyl)piperazine (3, 4.0 g, 15.4 mmol)and TEA (3.1 g, 30.9 mmol) in DCM (30 mL) at 0° C. was addeddi-tert-butyl dicarbonate (5.04 g, 23.1 mmol). The reaction mixture wasstirred at RT for 2 h. After completion of the reaction (TLC), reactionmixture was treated with water and extracted with DCM. The separatedorganic layer was washed with NaHCO₃ solution, brine solution, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to affordcrude product. The crude product was purified by column chromatographyto get the title compound (4.0 g, 72.2%); LCMS (ESI positive ion) m/z:calculated: 358.07; observed: 259.0 (M−99+1).

Step 4: Synthesis of tert-butyl4-(2-fluoro-4-thiomorpholinophenyl)piperazine-1-carboxylate (5): To astirred solution of tert-butyl4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate (4, 4.0 g, 11.1 mmol)and thiomorpholine (1.3 g, 12.3 mmol) in toluene (30 mL) was added XPhos(530 mg, 1.11 mmol) followed by NaO^(t)Bu (2.34 g, 24.4 mmol) in sealedtube. The reaction mixture was purged with N₂ gas and Pd(OAc)₂ (250 mg,1.11 mmol) was added. The reaction mixture was heated at 110° C. for 16h. After completion of the reaction (TLC), reaction mixture was treatedwith water and extracted with ethyl acetate. The separated organic layerwas washed with NaHCO₃ solution, brine solution, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford crude product.The crude product was purified by column chromatography to get the titlecompound (1.53 g, 33.9%); LCMS (ESI positive ion) m/z: calculated:381.19; observed: 382.1 (M+1).

Step 5: Synthesis of tert-butyl4-(2-fluoro-4-thiomorpholinophenyl)piperazine-1-carboxylate (6): To astirred solution of tert-butyl4-(2-fluoro-4-thiomorpholinophenyl)piperazine-1-carboxylate (5, 1.8 g,4.7 mmol) in acetic acid (20 mL) at 0° C. hydrogen peroxide (160.48 mg,4.7 mmol) was added. The reaction mixture was stirred at RT for 16 h.After completion of the reaction (TLC), reaction mixture was treatedwith 10% NaOH solution (aq.) and extracted with DCM. The separatedorganic layer was washed with NaHCO₃ solution, brine solution, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to affordcrude product. The crude product was purified by column chromatographyto get the title compound (1.2 g, 62.6%); LCMS (ESI positive ion) m/z:calculated: 397.18; observed: 398.1 (M+1).

Step 6: Synthesis of 4-(3-fluoro-4-(piperazin-1-yl)phenyl)thiomorpholine1-oxide (7): To a stirred solution of tert-butyl4-(2-fluoro-4-(1-oxidothiomorpholino)phenyl)piperazine-1-carboxylate (6,1.2 g, 3.0 mmol) in DCM (15 mL) at 0° C. TFA (330 mg, 9.0 mmol) wasadded. The reaction mixture was stirred at room temperature for 2 h.After completion of the reaction (TLC), reaction mixture wasconcentrated under reduced pressure. The residue was dissolved inmethanol and neutralized using Tosic acid scavenger resin to get thefree base (750 mg, 82.2%); LCMS (ESI positive ion) m/z: calculated:297.13; observed: 298.1 (M+1).

Step 7: Synthesis of5-amino-3-(2-(4-(2-fluoro-4-(1-oxidothiomorpholino)phenyl)-piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 126): To a stirred solution of1-(3-fluoro-4-(piperazin-1-yl)phenyl)piperidin-4-one (350 mg, 1.26 mmol)in DMF (5 mL) was added2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidin-1(2H)-yl)ethylmethanesulfonate (500 mg, 1.26 mmol) and DIPEA (815 mg, 6.31 mmol). Thereaction mixture was stirred at 120° C. for 16 h. After completion thereaction mass was concentrated under reduced pressure and recrystallizedwith acetonitrile and diethyl ether to get the pure5-amino-3-(2-(4-(2-fluoro-4-(1-oxidothiomorpholino)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]-triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 126) (150 mg, 19%); HPLC purity (XB0595TF): 95.08%; LCMS (ESIpositive ion) m/z: calculated: 597.17; observed: 598.2 (M+1); ¹H-NMR(400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (s, 1H), 7.24 (d, J=3.2 Hz,1H), 6.92-6.85 (m, 2H), 6.73-6.71 (m, 2H), 4.08-4.05 (m, 2H), 3.70-3.66(m, 2H), 3.53-3.50 (m, 2H), 2.93-2.86 (m, 7H), 2.74-2.63 (m, 7H).

Example 127:(S)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methylmethanesulfonate (7): To a stirred solution of(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (6, 2.5 g, 19 mmol) in DCM(30 mL) was added triethylamine (9.6 g, 95 mmol) and methane sulfonylchloride (4.33 g, 38 mmol) at 0° C. The reaction mixture was allowed tostir for 3 h at 0° C. The reaction was monitored by TLC and aftercompletion, the reaction mixture was diluted with water and extractedwith DCM. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄, filtered then concentrated under reduced pressure toafford the title compound as yellow gummy liquid (3.0 g, 75.4%); ¹H-NMR(400 MHz, CDCl₃): δ 4.39-4.43 (m, 1H), 4.25 (d, J=5.20 Hz, 2H),4.11-4.15 (m, 1H), 3.84-3.87 (m, 1H), 3.09-3.15 (m, 3H), 1.45 (s, 3H),1.43 (s, 3H).

Step 2: Synthesis of benzyl(R)-4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine-1-carboxylate(2): To a stirred solution of benzyl4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (1, 1 g, 2.9mmol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate(7, 1.15 g, 5.8 mmol) in DMF (20 mL) was added potassium carbonate (1.19g, 8.7 mmol) and reaction mixture was heated to 90° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion, thereaction mass was diluted with water and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and then concentrated under reduced pressure. The crudewas purified by column chromatography (30% EtOAc/hexane) to affordbenzyl(R)-4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine-1-carboxylate (2) as light brown solid (800 mg, 56.8%); LCMS(ESI positive ion) m/z: calculated: 462.20; observed: 463.0 (M+1).

Step 3: Synthesis of(R)-1-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluoro-phenyl)piperazine (3): To a stirred solution of benzyl(R)-4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine-1-carboxylate(2, 0.8 g, 1.73 mmol) in EtOAc (20 mL), 10% Pd/C (0.2 g) was added undernitrogen atmosphere. The reaction mixture was stirred under H₂atmosphere for 16 h. The progress of the reaction was monitored by TLC.After completion, the reaction mixture was filtered using celite toremove the Pd/C. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to get(R)-1-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine(3) as a brown gummy material (0.45 g, 76.2%); LCMS (ESI positive ion)m/z: calculated: 328.16; observed: 329.1 (M+1).

Step 4: Synthesis of(R)-5-amino-3-(2-(4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(4): To a stirred solution of(R)-1-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine (3, 0.45 g, 1.4 mmol) and2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (0.48 μg, 1.2 μmmol) in N,N-dimethylformamide (6 mL)was added DIPEA (0.71 g, 5.5 mmol) and the reaction mixture was stirredat 120° C. for 16 h. After completion of the reaction (TLC & LCMS), thesolvent was removed under reduced pressure. The reaction mass wastreated with water and extracted with ethyl acetate. Organic layer waswashed with saturated brine solution, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude product waspurified by column chromatography (14-16% MeOH/DCM) and it was furtherenriched by washing with 50% ACN/diethyl ether mixture to get the(R)-5-amino-3-(2-(4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onecompound (4) as light yellow solid (100 g, 13.1%); LCMS (ESI positiveion) m/z: calculated: 628.20; Observed; 629.0 (M+1); Step 5: Synthesisof(S)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)-piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 127): To a stirred solution of(R)-5-amino-3-(2-(4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e]l[1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(4, 50 mg, 0.08 mmol) in 1,4-dioxane (4 mL) at 0° C., 4 N HCl in dioxane(20 mL) was added. Reaction mixture was allowed to stir for 1 h at roomtemperature. The progress of the reaction was monitored by TLC. Afterthe completion of reaction, it was concentrated under reduced pressureto remove the solvent. The crude product was recrystallized usingacetonitrile to afford(S)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 127) as light brown solid (35 mg, 67.3%); HPLC purity(XB0595TF): 92.58%; LCMS (ESI positive ion) m/z: calculated: 588.17;observed: 589.2 (M+1); ¹H-NMR (400 MHz, DMSO-d6): δ 9.67 (brs, 1H), 8.42(brs, 2H), 7.97 (s, 1H), 7.35-7.26 (m, 2H), 6.86 (t, J=8.40 Hz, 1H),6.75-6.74 (m, 1H), 4.31 (m, 2H), 4.09-4.05 (m, 1H), 3.97-3.92 (m, 3H),3.77 (t, J=5.20 Hz, 1H), 3.43 (m, 2H), 3.29 (m, 2H), 3.06-2.99 (m, 2H).

Example 128:(R)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

Step 1: Synthesis of 5-amino-2,4-difluorophenol (2): To a stirredsolution of 2,4-difluoro-5-nitrophenol (1, 25 g, 0.143 mol) in EtOAc(200 mL), 10% Pd/C (4.55 g, 0.043 mol) was added. The reaction mixturewas stirred at RT under H₂ for 16 h. After the reaction completion(TLC), the reaction mixture was filtered by using celite bed, washedwith EtOAc (1000 mL) and concentrated under reduced pressure to afford5-amino-2,4-difluorophenol (2) as off brown solid (20.10 g, 94.6%); LCMS(ESI positive ion) m/z: calculated: 145.03; observed: 146.2 (M+1).

Step 2: Synthesis of 2,4-difluoro-5-(piperazin-1-yl)phenol (3): To astirred solution of 5-amino-2,4-difluorophenol (2, 20 g, 0.131 mol) insulfolane (30 mL) bis(2-chloroethyl) amine hydrogen chloride (31 g,0.170 mol) was added. The resulting mixture was stirred at 150° C. undernitrogen atmosphere for 16 h. It was cooled to RT and acetone was addedto the crude reaction mixture and stirred at 0° C. for 1 h. After 1 h,the precipitated solid was filtered and washed with chilled acetoneunder nitrogen atmosphere. The solid material was dried under vacuum toafford 2,4-difluoro-5-(piperazin-1-yl)phenol (3) as off white solid (23g, 80.3%); LCMS (ESI positive ion) m/z: calculated: 214.09; observed:215.1 (M+1).

Step 3: Synthesis of benzyl4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (4): To astirred solution of 2,4-difluoro-5-(piperazin-1-yl)phenol hydrochloride(3, 25 g, 0.117 mol), in THF (250 mL) was added NaHCO₃ (14.7 g, 0.175mol) and Cbz-Cl (16.66 mL, 0.117 mol) at 0° C. The reaction mixture wasstirred at RT for 16 h. The progress of the reaction was monitored byTLC. The reaction mixture was extracted with ethyl acetate and thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and then concentrated under reduced pressure. The crude obtainedwas purified by column chromatography (30% EtOAc/Hexane as eluent) toafford benzyl 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylateas white solid (20 g, 45.8%); LCMS (ESI positive ion) m/z: calculated:348.13; observed: 349.2 (M+1).

Step 4: Synthesis of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methylmethanesulfonate (10): To a stirred solution of(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (9, 12 g, 0.091 mol) in DCM(100 mL) was added triethylamine (37.76 mL, 0.272 mol) and methanesulfonyl chloride (8.4 mL, 0.109 mol) at 0° C. The reaction mixture wasallowed to stir for 3 h at 0° C. The reaction was monitored by TLC andafter completion, the reaction mixture was diluted with water andextracted with DCM. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄, filtered then concentrated under reducedpressure to afford the title compound as yellow gummy liquid (21.8 g,77.8%); LCMS (ESI positive ion) m/z: calculated: 210.06; observed: 211.0(M+1).

Step 5: Synthesis of benzyl(S)-4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine-1-carboxylate(5): To a stirred solution of benzyl4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (4. 10 g, 0.029mol) and (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate(10, 7.2 g, 0.034 mol) in DMF (70 mL) was added potassium carbonate(11.9 g, 0.086 mol) and reaction mixture was heated to 90° C. for 16 h.The progress of the reaction was monitored by TLC. After completion, thereaction mass was diluted with water and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and then concentrated under reduced pressure. The crudewas purified by column chromatography (30% EtOAc/hexane) to affordbenzyl(S)-4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine-1-carboxylate (5) as light brown solid (13 g, 70.50%); LCMS(ESI positive ion) m/z: calculated: 462.20; observed: 463.1 (M+1).

Step 6: Synthesis of(S)-1-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluoro-phenyl)piperazine (6): To a stirred solution of benzyl(S)-4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine-1-carboxylate(5, 13 g, 0.028 mol) in EtOAc (100 mL), 10% Pd/C (4 g) was added undernitrogen atmosphere. The reaction mixture was stirred under H₂atmosphere for 16 h. The progress of the reaction was monitored by TLC.After completion, the reaction mixture was filtered using celite toremove the Pd/C. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to get(S)-1-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine(6) as a brown gummy material (8.55 g, 93.0%); LCMS (ESI positive ion)m/z: calculated: 328.16; observed: 329.2 (M+1).

Step 7: Synthesis of(S)-5-amino-3-(2-(4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(7): To a stirred solution of(S)-1-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine(6, 7 g, 0.021 mol) and2-(5-amino-8-(furan-2-yl)-2-oxothiazolo-[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane sulfonate (7.6 μg, 0.019 mol) in N,N-dimethylformamide (50 mL)was added DIPEA (11.12 mL, 0.064 mol) and the reaction mixture wasstirred at 120° C. for 16 h. After completion of the reaction (TLC &LCMS), the solvent was removed under reduced pressure. The reaction masswas treated with water and extracted with ethyl acetate. Organic layerwas washed with saturated brine solution, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude product waspurified by column chromatography (14-16% MeOH/DCM) and it was furtherenriched by washing with 50% ACN/diethyl ether mixture to get the(S)-5-amino-3-(2-(4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onecompound (7) as light yellow solid (2.6 g, 17.8%); LCMS (ESI positiveion) m/z: calculated: 628.20; Observed; 629.2 (M+1).

Step 8: Synthesis of(R)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)-piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 128): To a stirred solution of(S)-5-amino-3-(2-(4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(7, 1.4 g, 2.23 mmol) in 1,4-dioxane (20 mL) at 0° C., 4 N HCl indioxane (20 mL) was added. Reaction mixture was allowed to stir for 1 hat room temperature. The progress of the reaction was monitored by TLC.After the completion of reaction, it was concentrated under reducedpressure to remove the solvent. The crude product was recrystallizedusing acetonitrile to afford(R)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(Compound 128) as white solid (1.2 g, 87%); HPLC purity (AM9010A3):95.05%; LCMS (ESI positive ion) m/z: calculated: 588.17; observed: 589.2(M+1); ¹H-NMR (400 MHz, DMSO-d6): δ 10.34 (brs, 1H), 8.40 (brs, 2H),7.95 (s, 1H), 7.33-7.24 (m, 2H), 6.87-6.82 (m, 1H), 6.73 (s, 1H), 4.31(m, 2H), 4.08-4.05 (m, 1H), 3.96-3.91 (m, 3H), 3.76 (m, 1H), 3.59 (m,2H), 3.51-3.48 (m, 2H), 3.42-3.38 (m, 2H), 3.29-3.27 (m, 2H), 3.14-3.08(m, 2H).

The Following Examples were Prepared According to Similar Procedures asThose Described for Examples Above:

Example 9:5-amino-8-(furan-2-yl)-3-(2-(4-(4-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 522.18; observed: 523.2 (M+1);HPLC purity (XB0595TF): 97.0%; ¹H NMR (400 MHz, CD₃OD): δ 7.79 (s, 1H),7.28 (d, J=3.2 Hz, 1H), 7.01 (d, J=8.1 Hz, 2H), 6.93 (d, J=9.2 Hz, 2H),6.69 (dd, J=1.6 & 3.2 Hz, 1H), 4.49 (m, 2H), 4.01 (t, J=4.4 Hz, 2H),3.86 (t, J=4.4 Hz, 2H), 3.67 (m, 4H).

Example 10:2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)phenoxy)aceticacid hydrochloride

LCMS (ESI positive ion) m/z: calculated: 536.16; observed: 536.8 (M+1);HPLC purity (XB0595TF): 93.00%; ¹H NMR (400 MHz, DMSO-d6): δ 12.92 (brs,1H), 9.72 (brs, 1H), 8.44 (brs, 2H), 7.97 (t, J=0.8 Hz, 1H), 7.26 (dd,J=0.6 & 3.2 Hz, 1H), 6.96-6.94 (m, 2H), 6.88-6.84 (m, 2H), 6.75 (dd,J=1.6 & 3.2 Hz, 1H), 4.60 (s, 2H), 4.32 (m, 2H), 3.92-3.90 (m, 2H),3.72-3.69 (m, 2H), 3.27-3.24 (m, 2H), 2.92 (m, 2H).

Example 11:2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)phenoxy)acetamide

LCMS (ESI positive ion) m/z: calculated: 535.58; Observed 535.8 (M+);HPLC Purity (XB0595TF): 92.65%; ¹H NMR (400 MHz, DMSO-d6): δ 8.31 (brs,2H), 7.94 (m, 1H), 7.44 (m, 1H), 7.36 (m, 1H), 7.23 (d, J=3.20 Hz, 1H),6.85 (t, J=4.40 Hz, 4H), 6.73 (s, 1H), 4.31 (s, 2H), 4.08 (m, 1H), 2.95(m, 4H), 2.68 (d, J=6.00 Hz, 2H), 2.61 (m, 3H), and 2.30 (s, 2H).

Example 12:5-amino-3-(2-(4-(4-(2,3-dihydroxypropoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 552.19; observed: 552.8 (M+1);HPLC purity (XB0595TF): 91.20%; ¹H NMR (400 MHz, DMSO-d6): δ 9.7 (brs,1H), 9.0 (brs, 1H), 8.41 (brs, 2H), 7.98 (dd, J=0.8 & 1.6 Hz, 1H), 7.27(m, 1H), 6.87 (m, 2H), 6.76-7.68 (m, 3H), 4.39 (m, 3H), 3.28 (m, 3H),2.85 (m, 4H).

Example 13:5-amino-3-(2-(4-(4-(2-aminoethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS (ESI positive ion) m/z: calculated: 521.6; Observed; 522.2 (M+1);HPLC Purity (XB0595TF): 96.52%; ¹H NMR (400 MHz, DMSO-d6): δ 8.41 (brs,2H), 8.23 (brs, 3H), 7.96 (dd, J=2 Hz, 1H), 7.25 (d, J=3.2 Hz, 1H), 6.99(d, J=9.20 Hz, 2H), 6.93 (d, J=2.40 Hz, 2H), 6.74 (t, J=1.60 Hz, 1H),4.33 (t, J=5.60 Hz, 2H), 4.12 (t, J=5.20 Hz, 2H), 3.88 (d, J=10.80 Hz,2H), 3.69 (d, J=12.00 Hz, 2H), 3.58 (m, 2H), and 3.14-3.20 (m, 6H).

Example 14:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzamide

LCMS (ESI positive ion) m/z: calculated: 505.56; Observed; 506.2 (M+1);HPLC purity (XB0595TF): 99.08%; ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (brs,2H), 7.95 (brs, 1H), 7.73 (brs, 3H), 7.24 (brs, 1H), 6.91-7.01 (m, 3H),6.73 (brs, 1H), 4.09 (brs, 2H), 3.19 (brs, 4H), and 2.69 (brs, 6H).

Example 15:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-methylbenzamide

LCMS (ESI positive ion) m/z: calculated: 519.58; Observed; 520.8 (M+1);HPLC purity (XB0595TF): 95.07%; ¹H NMR (400 MHz, DMSO-d6): δ 8.33 (brs,2H), 8.13 (d, J=4.40 Hz, 1H), 7.95 (s, 1H), 7.70 (d, J=8.60 Hz, 2H),7.24 (d, J=3.32 Hz, 1H), 6.91 (d, J=8.64 Hz, 2H), 6.73 (d, J=1.72 Hz,1H), 4.09 (t, J=6.16 Hz, 2H), 3.18 (m, 4H), 2.72-2.74 (m, 5H), and2.62-2.70 (m, 4H).

Example 16:5-amino-8-(furan-2-yl)-3-(2-(4-(4-(2-morpholinoethoxy)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 591.24; observed: 592.3 (M+1);HPLC purity (XB0595TF): 99.39%; ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (brs,2H), 7.95 (s, 1H), 7.24 (d, J=3.2 Hz, 1H), 6.85-6.79 (m, 4H), 6.73-6.72(m, 1H), 4.08 (t, J=6.0 Hz, 2H), 3.99 (t, J=5.6 Hz, 2H), 3.57 (t, J=4.0Hz, 4H), 2.94 (m, 4H), 2.71-2.62 (m, 8H), 2.46 (m, 4H).

Example 17:5-amino-3-(2-(4-(4-(2-(dimethylamino)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 549.22; observed: 549.8 (M+1);HPLC purity (XB0595TF): 92.54%; ¹H NMR (400 MHz, DMSO-d6): δ 8.31 (brs,2H), 7.95 (s, 1H), 7.24 (d, J=2.8 Hz, 1H), 6.85-6.79 (m, 4H), 6.73 (m,1H), 4.08 (t, J=6.00 Hz, 2H), 3.95 (t, J=6.0 Hz, 2H), 2.94 (m, 4H), 2.69(m, 2H), 2.61 (m, 4H), 2.56 (t, J=6.0 Hz, 2H), 2.19 (s, 6H).

Example 18:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzenesulfonamide

LCMS (ESI positive ion) m/z: calculated: 541.13; observed: 542.2 (M+1);HPLC purity (XB0595TF): 90.64%; ¹H NMR (400 MHz, DMSO-d6): δ 8.31 (brs,2H), 7.94 (d, J=0.40 Hz, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.23 (d, J=3.6 Hz,1H), 7.07-6.98 (m, 4H), 6.72 (m, 1H), 4.08 (m, 2H), 3.20 (m, 4H),2.70-2.61 (m, 6H).

Example 19:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-methylbenzenesulfonamide

LCMS (ESI positive ion) m/z: calculated: 555.15; observed: 556.3 (M+1);HPLC purity (XB0595TF): 93.45%; ¹H NMR (400 MHz, DMSO-d6): δ 8.33 (brs,2H), 7.95 (s, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.24 (d, J=3.2 Hz, 1H), 7.11(q, J=4.80 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.73 (m, 1H), 4.10 (t, J=5.6Hz, 2H), 3.24 (m, 4H), 2.73-2.62 (m, 6H), 2.34 (d, J=5.20 Hz, 3H).

Example 20:5-amino-8-(furan-2-yl)-3-(2-(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS: (ESI positive ion) m/z: calculated: 540.62; Observed; 541.3 (M+1);HPLC purity (XB0595TF): 98.58%; ¹H NMR (400 MHz, DMSO-d6): δ 8.31 (brs,2H), 7.95 (s, 1H), 7.67 (d, J=8.80 Hz, 2H), 7.24 (d, J=3.20 Hz, 1H),7.05 (d, J=8.80 Hz, 2H), 6.73 (q, J=2.00 Hz, 1H), 4.11-4.05 (m, 2H),3.27 (m, 4H), 3.08 (m, 3H), 2.71 (t, J=6.00 Hz, 2H), and 2.51 (m, 4H).

Example 21:5-amino-8-(furan-2-yl)-3-(2-(4-(4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 524.14; observed: 525.1; HPLCpurity (XB0595TF): 98.99%; ¹H NMR: (400 MHz, DMSO-d6): δ 8.32 (brs, 2H),7.95 (s, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.24 (d, J=3.2 Hz, 1H), 7.06 (d,J=8.8 Hz, 2H), 6.73 (dd, J=1.6 & 3.2 Hz, 1H), 4.09 (t, J=6.0 Hz, 2H),3.18 (m, 4H), 2.72-2.62 (m, 9H).

Example 22:3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzamide

LCMS (ESI positive ion) m/z: calculated: 505.16; observed: 506.2 (M+1);HPLC purity (XB0595TF): 90.01%; ¹H NMR (400 MHz, DMSO-d6): δ 8.33 (brs,2H), 7.95 (s, 1H), 7.89 (s, 1H), 7.38 (s, 1H), 7.26-7.23 (m, 4H), 7.05(m, 1H), 6.73 (m, 1H), 4.10 (t, J=6.0 Hz, 2H), 3.12 (m, 4H), 2.73-2.63(m, 6H).

Example 23:5-amino-8-(furan-2-yl)-3-(2-(4-(3-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 522.18; observed: 522.8 (M+1);HPLC purity (XB0595TF): 92.67%; ¹H NMR (400 MHz, DMSO-d6): δ 9.98 (brs,1H), 8.43 (brs, 2H), 7.96 (t, J=0.8 Hz, 1H), 7.26 (d, J=0.8 Hz, 1H),7.16 (t, J=8.0 Hz, 1H), 6.74 (dd, J=1.6 & 3.2 Hz, 1H), 6.57-6.52 (m,2H), 6.46 (dd, J=2.0 & 8.0 Hz, 1H), 4.31 (t, J=5.6 Hz, 2H), 3.97-3.85(m, 6H), 3.70 (t, J=5.2 Hz, 2H), 3.60 (m, 2H), 3.03 (m, 2H).

Example 24:5-amino-3-(2-(4-(2-fluoro-4-(2-oxo-2-(piperazin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS: (ESI positive ion); m/z: calculated: 622.68; Observed; 623.2(M+1); HPLC purity (XB0595TF): 98.01%; ¹H NMR (400 MHz, DMSO-d6): δ 8.90(brs, 2H), 8.41 (brs, 2H), 7.97 (d, J=0.80 Hz, 1H), 7.26 (t, J=5.20 Hz,1H), 7.00 (d, J=8.40 Hz, 1H), 6.90 (d, J=13.60 Hz, 1H), 6.75-6.74 (m,2H), 4.86 (m, 2H), 4.30 (b s, 2H), 3.94 (b s, 2H), 3.64 (t, J=4.80 Hz,4H), 3.49 (t, J=5.20 Hz, 2H), 3.22 (m, 4H), 3.18 (brs, 2H), 3.1 (brs,2H), and 2.94 (brs, 2H).

Example 25:5-amino-3-(2-(4-(2-fluoro-4-(piperidin-4-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS (ESI positive ion) m/z: calculated: 593.23; observed: 594.2 (M+1);HPLC purity (XB0595TF): 96.25%; ¹H NMR (400 MHz, DMSO-d6): δ 10.25 (brs,1H), 8.85 (brs, 1H), 8.55 (brs, 1H), 8.41 (brs, 2H), 7.96 (s, 1H), 7.26(d, J=3.2 Hz, 1H), 7.03 (t, J=9.60 Hz, 1H), 6.88 (dd, J=2.4 & 14.0 Hz,1H), 6.74 (m, 2H), 4.32 (m, 2H), 4.06 (m, 4H), 3.62 (m, 2H), 3.39 (m,2H), 3.28 (m, 4H), 3.05 (t, J=12.4 Hz, 2H), 2.90 (m, 2H), 2.01 (m, 1H),1.89 (m, 2H), 1.47 (m, 2H).

Example 26:5-amino-3-(2-(4-(2-fluoro-4-(piperazine-1-carbonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS (ESI positive ion) m/z: calculated: 592.21; observed: 592.9 (M+1);HPLC purity (XB0595TF): 95.39%; ¹H NMR (400 MHz, DMSO-d6): δ 10.30 (brs,1H), 9.22 (brs, 2H), 8.42 (brs, 2H), 7.96 (s, 1H), 7.34 (dd, J=1.6 &12.8 Hz, 1H), 7.28 (m, 2H), 7.14 (t, J=8.8 Hz, 1H), 6.74 (dd, J=1.6 &3.2 Hz, 1H), 4.33 (m, 2H), 3.96-3.88 (m, 2H), 3.17 (m, 6H), 2.32 (m,6H).

Example 27:5-amino-3-(2-(4-(2-fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS (ESI positive ion) m/z: calculated: 608.24; observed: 609.0 (M+1);HPLC purity (XB0595TF): 91.12%; ¹H NMR (400 MHz, DMSO-d6): δ 10.52 (brs,1H), 9.71 (brs, 2H), 8.42 (brs, 2H), 7.97 (s, 1H), 7.26 (d, J=3.6 Hz,1H), 7.10-6.99 (m, 2H), 6.84-6.74 (m, 2H), 4.40 (t, J=4.4 Hz, 2H), 4.33(t, J=4.8 Hz, 2H), 3.92 (m, 2H), 3.45-3.40 (m, 4H), 3.24 (m, 3H), 3.11(m, 3H).

Example 28:5-amino-3-(2-(4-(2-fluoro-4-(piperazin-1-ylsulfonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS (ESI positive ion) m/z: calculated: 628.18; observed: 628.8 (M+1);HPLC purity (XB0595TF): 90.55%; ¹H NMR (400 MHz, DMSO-d₆): δ 10.91 (brs,1H), 9.26 (brs, 2H), 8.42 (brs, 2H), 7.96 (s, 1H), 7.64-7.54 (m, 2H),7.3 (t, J=8.4 Hz, 1H), 7.25 (m, 1H), 6.74 (s, 1H), 4.33 (m, 2H), 4.07(m, 8H), 3.95 (m, 2H), 3.76 (m, 2H), 3.60 (m, 2H), 3.33 (m, 4H).

Example 29:5-amino-3-(2-(4-(2-fluoro-4-(methylsulfonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS: (ESI positive ion) m/z: calculated: 558.61; Observed; 559.8 (M+1);HPLC purity (XB0595TF): 97.88%; ¹H NMR (400 MHz, DMSO-d6): δ 8.31 (brs,2H), 7.95 (s, 1H), 7.62 (t, J=8.40 Hz, 2H), 7.24 (d, J=3.20 Hz, 1H),7.16 (t, J=8.40 Hz, 1H), 6.73 (s, 1H), 4.11-4.04 (m, 2H), 3.18 (s, 3H),3.12 (brs, 4H), and 2.73-2.65 (m, 6H).

Example 30:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-aminoethyl)-3-fluorobenzamidehydrochloride

LCMS: (ESI positive ion) m/z: calculated: 566.62; Observed; 567.0 (M+1);HPLC purity (XB0595TF): 99.16%; ¹H NMR (400 MHz, DMSO-d6): δ 10.92 (brs,1H), 8.79 (t, J=5.60 Hz, 1H), 8.41 (brs, 2H), 8.10 (s, 3H), 7.97-7.96(m, 1H), 7.79-7.75 (m, 2H), 7.26-7.25 (m, 1H), 7.16 (t, J=9.20 Hz, 1H),6.74 (q, J=1.60 Hz, 1H), 4.33 (t, J=5.20 Hz, 2H), 3.94-3.92 (m, 2H),3.69-3.66 (m, 2H), 3.59 (m, 2H), 3.53-3.49 (m, 2H), 3.26 (m, 4H), and2.97 (m, 2H).

Example 31:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylamino)ethyl)benzamidehydrochloride

LCMS: (ESI positive ion) m/z: calculated: 580.21; Observed; 581.2 (M+1);HPLC purity (XB0595TF): 98.97%; ¹H NMR (400 MHz, DMSO-d6): δ 10.81 (b s,1H), 8.94 (brs, 2H), 8.83 (t, J=4.80 Hz, 1H), 8.41 (br s, 2H), 7.97 (s,1H), 7.80-7.76 (m, 2H), 7.26 (d, J=3.20 Hz, 1H), 7.16 (t, J=8.80 Hz,1H), 6.74 (q, J=1.20 Hz, 1H), 4.33 (m, 2H), 3.93 (d, J=9.20 Hz, 2H),3.68 (m, 6H), 3.26 (t, J=11.60 Hz, 4H), 3.09-3.08 (m, 2H), and 2.563 (t,J=4.8 Hz, 3H).

Example 32:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3-fluorobenzamide

LCMS (ESI positive ion) m/z: calculated: 594.23; observed: 595.0 (M+1);HPLC purity (XB0595TF.M): 96.47%; ¹H NMR (400 MHz, DMSO-d6): δ 8.30 (m,3H), 7.95 (d, J=1.20 Hz, 1H), 7.62-7.57 (m, 2H), 7.24 (d, J=3.20 Hz,1H), 7.02 (t, J=8.80 Hz, 1H), 6.73 (dd, J=1.6 & 3.2 Hz, 1H), 4.09 (t,J=6.40 Hz, 2H), 3.04 (m, 4H), 2.72 (d, J=6.0 Hz, 2H), 2.66 (m, 4H), 2.42(t, J=6.00 Hz, 2H), 2.19 (s, 6H).

Example 33:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide

LCMS (ESI positive ion) m/z: calculated: 567.18; observed: 567.8 (M+1);HPLC purity (XB0595TF): 98.37%; ¹H NMR (400 MHz, DMSO-d6): δ 8.34 (brs,2H), 7.95 (s, 1H), 7.63 (s, 2H), 7.24 (m, 1H), 7.01-6.95 (m, 1H), 6.73(m, 1H), 4.72 (m, 2H), 4.57 (m, 2H), 4.09 (m, 2H), 3.48 (m, 6H), 3.03(m, 4H).

Example 34:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-3-fluorobenzamide

LCMS (ESI positive ion) m/z: calculated: 597.19; observed: 597.8 (M+1);HPLC purity (XB0595TF): 95.11%; ¹H NMR (400 MHz, DMSO-d6): δ 8.36-8.31(m, 4H), 7.95 (s, 1H), 7.64-7.60 (m, 2H), 7.24 (d, J=3.2 Hz, 1H), 7.02(m, 1H), 6.73 (dd, J=1.6 & 3.2 Hz, 1H), 4.80 (m, 1H), 4.59 (m, 2H), 4.09(t, J=6.0 Hz, 2H), 3.61 (m, 4H), 3.10 (m, 4H), 2.65 (m, 4H).

Example 35:2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)aceticacid

LCMS (ESI positive ion) m/z: calculated: 554.15; observed: 555.0 (M+1);HPLC purity (XB0595TF): 98.30%; ¹H NMR (400 MHz, DMSO-d6): δ 10.20 (brs,1H), 8.42 (brs, 2H), 7.97 (t, J=0.8 Hz, 1H), 7.26 (d, J=3.6 Hz, 1H),7.03 (t, J=9.2 Hz, 1H), 6.88 (dd, J=2.8, 14.0 Hz, 1H), 6.75-6.74 (m,2H), 4.67 (s, 2H), 4.31 (m, 2H), 3.91 (m, 2H), 3.60 (m, 2H), 3.42 (m,2H), 3.28 (q, J=10.0 Hz, 2H), 3.05 (t, J=12.00 Hz, 2H).

Example 36:2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3,5-difluorophenoxy)aceticacid

LCMS (ESI positive ion) m/z: calculated: 572.14; observed: 572.8 (M+1);HPLC purity (XB0595TF): 95.07%; ¹H NMR (400 MHz, DMSO-d6): δ 9.83 (brs,1H), 8.41 (brs, 2H), 7.97 (dd, J=0.8 & 2.0 Hz, 1H), 7.26 (dd, J=0.80 &3.2 Hz, 1H), 6.78-6.74 (m, 3H), 4.72 (s, 2H), 4.31 (m, 2H), 3.88 (m,2H), 3.60 (m, 2H), 3.25 (m, 4H).

Example 37:2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoicacid

LCMS (ESI positive ion) m/z: calculated: 568.17; observed: 568.8 (M+1);HPLC (XB0595TF): 95.55%; ¹H NMR (400 MHz, DMSO-d6): δ 10.15 (brs, 1H),8.41 (brs, 2H), 7.96 (s, 1H), 7.26 (s, 1H), 7.03 (t, J=9.60 Hz, 1H),6.82 (d, J=14.00 Hz, 1H), 6.74 (d, J=1.60 Hz, 1H), 6.67 (d, J=8.40 Hz,1H), 4.83 (q, J=6.80 Hz, 1H), 4.32 (m, 2H), 3.91 (m, 2H), 3.59 (m, 2H),3.40 (m, 2H), 3.28 (m, 2H), 3.04 (m, 2H), 1.48 (t, J=6.4 Hz, 3H);

Examples 38 and 53:(S)-2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoicacid and(R)-2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoicacid

The racemic mixture of the products, prepared as described for theExamples above (135 mg) was subjected to chiral separation (0.08 gsample was dissolved in 10 mL of ethanol), Phenomenex Lux C4 mobilephase: 0.1% TFA in n-hexane:ethanol (30:70), flow rate: 1.0 mL/min; toyield 13 mg of peak 1(S)-2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoicacid and 13 mg of peak 2((R)-2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoicacid) respectively. Note: Peak 1 was arbitrarily considered as (S)isomer and peak 2 was considered as (R) isomer.

(S)-2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoicacid. LCMS (ESI positive ion) m/z: calculated: 568.17; observed: 568.9(M+1); HPLC purity (XB0595TF): 95.79%; Chiral HPLC purity: 100%; ¹H-NMR(400 MHz, DMSO-d6): δ 13.03 (brs, 1H), 9.21 (brs, 1H), 8.41 (brs, 2H),7.96 (s, 1H), 7.26 (s, 1H), 7.04 (m, 1H), 6.82 (m, 1H), 6.75 (s, 1H),6.67 (m, 1H), 4.82 (q, J=5.2 Hz, 1H), 4.31 (m, 2H), 3.97 (m, 2H), 3.63(m, 2H), 2.93 (m, 2H), 1.48 (d, J=5.60 Hz, 3H).

(R)-2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoicacid. LCMS (ESI positive ion) m/z: calculated: 568.17; observed: 569.0(M+1); HPLC purity (XB0595TF): 98.05%; Chiral HPLC purity: 95.46%;¹H-NMR (400 MHz, DMSO-d6): δ 13.03 (brs, 1H), 9.25 (brs, 1H), 8.41 (brs,2H), 7.97 (s, 1H), 7.26 (s, 1H), 7.03 (m, 1H), 6.82 (m, 1H), 6.75 (s,1H), 6.67 (m, 1H), 4.82 (q, J=6.4 Hz, 1H), 4.30 (m, 2H), 3.96 (m, 2H),3.62 (m, 2H), 3.30 (m, 2H), 2.93 (m, 2H), 1.48 (d, J=6.0 Hz, 3H).

Example 39:2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-2-methylpropanoicacid hydrochloride

LCMS (ESI positive ion) m/z: calculated: 582.61; Observed; 582.8 (M+);HPLC purity (XB0595TF): 90.46%; ¹H NMR (400 MHz, DMSO-d6): δ 10.9 (br s,1H), 8.40 (brs, 2H), 7.96 (d, J=1.20 Hz, 1H), 7.25-7.26 (m, 1H), 7.01(t, J=10.00 Hz, 1H), 6.75-6.73 (m, 2H), 6.65-6.63 (m, 1H), 4.32 (t,J=5.60 Hz, 2H), 3.88 (d, J=11.20 Hz, 2H), 3.57 (d, J=4.00 Hz, 2H), 3.41(t, J=8.80 Hz, 2H), 3.25 (t, J=9.60 Hz, 2H), 3.13 (t, J=11.60 Hz, 2H),and 1.48 (s, 6H).

Example 40:3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)propanoicacid

LCMS (ESI positive ion) m/z: calculated: 553.18; observed: 552.9; HPLCpurity (XB0595TF): 93.92%; ¹H NMR (400 MHz, DMSO-d6): δ 9.62 (brs, 1H),8.41 (brs, 2H), 7.96 (m, 1H), 7.25 (m, 1H), 7.10 (m, 1H), 6.99 (m, 2H),6.74 (dd, J=2.0 & 3.6 Hz, 1H), 4.32 (m, 2H), 3.95 (m, 2H), 3.28 (m, 2H),2.99 (m, 2H), 2.32 (m, 2H).

Example 41:4-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)butanoicacid hydrochloride

LCMS: (ESI positive ion); m/z: calculated: 582.61; Observed; 582.3(M+1); HPLC purity (XB0595TF): 96.04%; ¹H NMR (400 MHz, DMSO-d6): δ10.31(br s, 1H) 8.41 (brs, 2H), 7.97 (d, J=0.80 Hz, 1H), 7.26 (d, J=3.20 Hz,1H), 7.02 (t, J=9.60 Hz, 1H), 6.87 (q, J=2.40 Hz, 1H), 6.75-6.72 (m,2H), 4.32 (m, 2H), 3.96-3.89 (m, 4H), 3.59 (m, 2H), 3.40 (d, J=11.60 Hz,2H), 3.28 (d, J=10.00 Hz, 2H), 3.06-3.03 (m, 2H), 2.36 (t, J=7.20 Hz,2H), and 1.91 (t, J=6.80 Hz, 2H).

Example 42:2-(3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,6-difluorophenoxy)aceticacid hydrochloride

LCMS (ESI positive ion); m/z: calculated: 572.55; Observed; 573.0 (M+1);HPLC purity (XB0595TF): 93.35%; ¹H NMR (400 MHz, DMSO-d6): δ 10.41 (brs,1H), 8.42 (brs, 2H), 7.97 (t, J=0.96 Hz, 1H), 7.27 (d, J=4.04 Hz, 1H),7.07 (t, J=9.40 Hz, 1H), 6.81-6.78 (m, 1H), 6.75-6.74 (m, 1H), 4.77 (m,2H), 4.32 (d, J=5.20 Hz, 2H), 3.92 (d, J=8.84 Hz, 2H), 3.60 (m, 2H),3.46 (d, J=12.04 Hz, 2H), 3.29 (d, J=9.16 Hz, 2H), and 3.10 (t, J=11.28Hz, 2H).

Example 43:2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)aceticacid hydrochloride

LC-MS: (ESI positive ion); m/z: calculated: 572.55; Observed; 573.0(M+1); HPLC purity (XB0595TF): 96.60%; ¹H NMR (400 MHz, DMSO-d6): δ13.06 (brs, 1H), 10.23 (brs, 1H), 8.40 (brs, 2H), 7.96-7.96 (m, 1H),7.33 (t, J=11.60 Hz, 1H), 7.25 (d, J=3.20 Hz, 1H), 6.82 (t, J=8.80 Hz,1H), 6.73-6.75 (m, 1H), 4.79 (s, 2H), 4.32 (m, 2H), 3.89-3.92 (m, 2H),3.60 (brs, 2H), 3.49-3.46 (m, 2H), 3.30-3.27 (m, 2H),), and 3.07 (t,J=11.6 Hz, 2H).

Example 44:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorobenzoicacid

LCMS (ESI positive ion) m/z: calculated: 524.14; observed: 525.0; HPLCpurity (XB0595TF): 89.07%; ¹H NMR: (400 MHz, DMSO-d6): δ 12.80 (brs,1H), 8.30 (brs, 2H), 7.95 (dd, J=0.8 & 1.6 Hz, 1H), 7.66 (dd, J=2.0 &8.4 Hz, 1H), 7.54 (dd, J=2.0 & 14.0 Hz, 1H), 7.23 (dd, J=0.8 & 3.2 Hz,1H), 7.04 (t, J=8.8 Hz, 1H), 6.73 (dd, J=1.6 & 3.2 Hz, 1H), 4.08 (t,J=6.0 Hz, 2H), 3.08 (m, 4H), 2.73-2.65 (m, 6H).

Example 45:2-((2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)amino)acetamidehydrochloride

LCMS: (ESI positive ion); m/z: calculated: 596.64; Observed; 597.0(M+1); HPLC purity (XB0595TF): 94.28%; ¹H NMR (400 MHz, DMSO-d6): δ10.62 (brs, 1H), 9.12 (brs, 2H), 7.96 (t, J=0.80 Hz, 1H), 7.92 (s, 1H),7.58 (brs, 1H), 7.26 (d, J=3.20 Hz, 1H), 7.07 (t, J=9.60 Hz, 1H), 6.96(dd, J=2.80, 13.60 Hz, 1H), 6.81-6.78 (m, 2H), 4.33-4.32 (m, 2H), 4.24(t, J=5.20 Hz, 2H), 3.76-3.77 (m, 2H), 3.59 (s, 2H), 3.42-3.35 (m, 8H),and 3.118 (m, 2H).

Example 46:2-((2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)(methyl)amino)acetamide

LCMS (ESI positive ion) m/z: calculated: 610.22; observed: 611.0 (M+1);HPLC purity (XB0595TF): 99.25%; ¹H NMR (400 MHz, DMSO-d6): δ 8.30 (brs,2H), 7.95 (d, J=0.8 Hz, 1H), 7.24 (m, 1H), 7.16 (brs, 1H), 7.11 (brs,1H), 6.93 (d, J=9.6 Hz, 1H), 6.79 (dd, J=2.8 & 14.0 Hz, 1H), 6.73 (dd,J=1.6 & 3.2 Hz, 1H), 6.67 (m, 1H), 4.08-4.02 (m, 4H), 2.96 (s, 2H), 2.85(m, 4H), 2.75-2.63 (m, 8H), 2.31 (s, 3H).

Example 47:5-amino-3-(2-(4-(2-fluoro-4-(piperidin-4-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS (ESI positive ion) m/z: calculated: 579.22; observed: 580.0 (M+1);HPLC purity (XB0595TF): 95.3%; ¹H NMR (400 MHz, DMSO-d6): δ 10.29 (brs,1H), 8.89 (brs, 2H), 8.42 (brs, 2H), 7.97 (s, 1H), 7.26 (d, J=3.2 Hz,1H), 7.06-6.97 (m, 2H), 6.82-6.75 (m, 2H), 4.60 (m, 1H), 4.32 (m, 2H),3.92 (m, 2H), 3.60 (m, 2H), 3.41 (m, 2H), 3.29-3.20 (m, 4H), 3.06 (m,4H), 2.06 (m, 2H), 1.81 (m, 2H).

Example 48:5-amino-3-(2-(4-(2-fluoro-4-(pyrrolidin-3-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS (ESI positive ion) m/z: calculated: 565.20; observed: 566.0 (M+1);HPLC purity (XB0595TF): 97.96%; ¹H NMR (400 MHz, DMSO-d6): δ 10.72 (brs,1H), 9.72 (brs, 1H), 9.50 (brs, 1H), 8.42 (brs, 2H), 7.97 (s, 1H), 7.26(d, J=3.6 Hz, 1H), 7.05 (t, J=9.2 Hz, 1H), 6.95 (dd, J=2.4 & 13.6 Hz,1H), 6.80-6.74 (m, 2H), 5.10 (m, 1H), 4.33 (m, 2H), 3.90 (m, 2H), 3.59(m, 2H), 3.42 (m, 3H), 3.28 (m, 5H), 3.13 (m, 2H), 2.14 (m, 2H).

Example 49:3-(2-(4-(4-((1H-1,2,4-triazol-3-yl)methoxy)-2-fluorophenyl)piperazin-1-yl)ethyl)-5-amino-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 577.17; observed: 578.2 (M+1);HPLC purity (XB0595TF): 93.44%; ¹H NMR (400 MHz, DMSO-d6): δ 14.09 (brs,1H), 8.56 (brs, 1H), 8.31 (brs, 3H), 7.96 (s, 1H), 7.24 (d, J=3.20 Hz,1H), 6.96-6.90 (m, 2H), 6.79-6.74 (m, 2H), 5.08 (s, 2H), 4.08 (t, J=6.0Hz, 2H), 2.86 (m, 4H), 2.72-2.68 (m, 6H).

Example 50:2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-(methylamino)ethyl)acetamidehydrochloride

LCMS (ESI positive ion) m/z: calculated: 610.22; observed: 611.0 (M+1);HPLC purity (XB0595TF): 99.20%; ¹H NMR (400 MHz, DMSO-d6): δ 10.36 (brs,1H), 8.79 (brs, 2H), 8.42 (brs, 3H), 7.97 (t, J=0.8 Hz, 1H), 7.26 (d,J=3.2 Hz, 1H), 7.06 (t, J=9.6 Hz, 1H), 6.96 (dd, J=2.4 & 13.6 Hz, 1H),6.80 (m, 1H), 6.74 (t, J=1.6 Hz, 1H), 4.50 (s, 2H), 4.33 (m, 2H), 3.59(m, 2H), 3.46-3.40 (m, 4H), 3.28 (m, 2H), 3.10-2.99 (m, 4H), 2.55 (s,3H).

Example 51:2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-(dimethylamino)ethyl)acetamide

LCMS (ESI positive ion) m/z: calculated: 624.24; observed: 625.0 (M+1);HPLC purity (XB0595TF): 97.22%; ¹H NMR (400 MHz, DMSO-d6): δ 8.31 (brs,2H), 7.95 (m, 2H), 7.24 (d, J=3.2 Hz, 1H), 6.94 (t, J=9.6 Hz, 1H), 6.83(d, J=14.0 Hz, 1H), 6.74-6.69 (m, 2H), 4.42 (s, 2H), 4.08 (m, 2H), 3.20(q, J=6.4 Hz, 2H), 2.86 (m, 4H), 2.70-2.63 (m, 6H), 2.29 (t, J=6.4 Hz,2H), 2.13 (s, 6H).

Example 52:2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-aminoethyl)acetamidehydrochloride

LCMS (ESI positive ion) m/z: calculated: 596.21; observed: 597.0 (M+1);HPLC purity (XB0595TF): 93.18%; ¹H NMR (400 MHz, DMSO-d6): δ 10.40 (brs,1H), 8.39 (brs, 3H), 7.97 (m, 3H), 7.26 (dd, J=0.8 & 3.2 Hz, 1H), 7.06(t, J=9.6 Hz, 1H), 6.95 (dd, J=2.4 & 13.6 Hz, 1H), 6.81-6.78 (m, 2H),4.49 (s, 2H), 4.32 (t, J=5.2 Hz, 2H), 3.90 (m, 2H), 3.60 (m, 2H), 3.40(m, 4H), 3.28 (a, J=10.00 Hz, 2H), 3.08 (m, 2H), 2.90 (m, 2H).

Example 54:2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)acetamide

LCMS (ESI positive ion) m/z: calculated: 553.16; observed: 554.0 (M+1);HPLC purity (XB0595TF): 95.07%; ¹H NMR (400 MHz, DMSO-d6): δ 9.43 (brs,1H), 8.41 (brs, 2H), 7.97 (s, 1H), 7.52 (brs, 1H), 7.40 (brs, 1H), 7.27(m, 1H), 7.05 (t, J=9.20 Hz, 1H), 6.91-6.87 (m, 1H), 6.75 (m, 2H), 4.41(s, 2H), 4.31 (m, 2H), 3.97 (m, 2H), 3.31 (m, 4H), 2.96 (m, 4H).

Example 55:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-methyl-N-(2-(methylamino)ethyl)benzamidehydrochloride

LCMS (ESI positive ion) m/z: calculated: 594.23; observed: 595.2 (M+1);HPLC purity (XB0595TF): 93.61%; ¹H NMR (400 MHz, DMSO-d6): δ 10.13 (brs,1H), 8.63 (brs, 2H), 8.42 (brs, 2H), 7.97 (s, 1H), 7.40 (m, 1H),7.32-7.26 (m, 2H), 7.14 (t, J=8.80 Hz, 1H), 6.75 (dd, J=0.8 & 3.2 Hz,1H), 4.35 (m, 2H), 3.98 (m, 2H), 3.67 (m, 6H), 3.15 (m, 6H), 2.96 (s,3H).

Example 56:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3-fluoro-N-methylbenzamide

LCMS (ESI positive ion) m/z: calculated: 608.70; Observed; 609.0 (M+1);HPLC Purity (XB0595TF): 99.46%; ¹H NMR (400 MHz, DMSO-d6): δ 8.31 (s,2H), 7.95 (s, 1H), 7.24 (d, J=3.36 Hz, 1H), 7.18-7.12 (m, 2H), 7.00 (t,J=8.48 Hz, 1H), 6.74-6.73 (m, 1H), 4.09 (t, J=12.60 Hz, 2H), 3.37-3.30(m, 2H), 3.01-2.93 (m, 4H), 2.91 (s, 3H), 2.73-2.62 (m, 8H), 2.22 (m,3H), and 2.02 (m, 3H).

Example 57:(R)-4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(1-(dimethylamino)propan-2-yl)-3-fluorobenzamide

LCMS (ESI positive ion) m/z: calculated: 608.24; observed: 609.3 (M+1);HPLC purity (XB0595TF): 98.79%; ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (brs,2H), 8.02 (m, 1H), 7.95 (s, 1H), 7.62-7.59 (m, 2H), 7.24 (d, J=3.2 Hz,1H), 7.02 (t, J=8.8 Hz, 1H), 6.74 (m, 1H), 4.09 (m, 3H), 3.04 (m, 4H),2.73-2.66 (m, 6H), 2.15 (m, 6H), 1.11 (d, J=6.4 Hz, 3H).

Example 58:2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-methyl-N-(2-(methylamino)ethyl)acetamidehydrochloride

LCMS (ESI positive ion) m/z: calculated: 624.24; observed: 625.0 (M+1);HPLC purity (XB0595TF): 92.37%; ¹H NMR (400 MHz, DMSO-d6): δ 10.10 (brs,1H), 8.63 (brs, 2H), 8.41 (brs, 1H), 7.96 (dd, J=0.8 & 1.6 Hz, 1H), 7.35(d, J=2.4 Hz, 1H), 7.06-6.90 (m, 2H), 6.78-6.74 (m, 2H), 4.81 (s, 2H),4.32 (m, 2H), 3.91 (d, J=10.80 Hz, 2H), 3.59 (m, 4H), 3.30 (m, 2H), 3.06(m, 3H), 3.00 (s, 3H), 2.60-2.55 (m, 3H).

Example 59:2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-2-methylpropanoicacid hydrochloride

LCMS: (ESI positive ion); m/z: calculated: 600.60; Observed; 601.0(M+1); HPLC purity (XB0595TF): 97.84%; ¹H NMR (400 MHz, DMSO-d6): δ10.30 (brs, 1H), 8.40 (brs, 2H), 7.96 (brs, 1H), 7.34 (t, J=11.20 Hz,1H), 7.26 (d, J=3.20 Hz, 1H), 6.80 (t, J=8.40 Hz, 1H), 6.79-6.73 (m,1H), 4.32 (m, 2H), 3.93-3.90 (m, 2H), 3.60 (t, J=6.40 Hz, 2H), 3.46-3.43(m, 2H), 3.30-3.28 (m, 2H), 3.03 (t, J=11.20 Hz, 2H), and 1.45 (s, and6H).

Examples 60 and 61:(S)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoicacid and(R)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoicacid

The racemic mixture of the products, prepared as described for theExamples above (0.08 g) was subjected to chiral separation (0.08 gsample was dissolved in 10 ml of ethanol), column-chiralpak AD-H, andmobile phase: 0.1% diethylamine in n-hexane: ethanol (70:30), flow rate:1.0 mL/min; to yield 10 mg of peak 1((S)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoicacid) and 13 mg of peak 2((R)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoicacid) respectively. Note: Peak 1 was arbitrarily attributed as (S)isomer and peak 2 was considered as (R) isomer.

(S)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoicacid

LCMS (ESI positive ion) m/z: calculated: 586.16; observed: 587.2 (M+1);HPLC purity (XB0595TF): 99.69%; Chiral HPLC purity: 100%; ¹H NMR (400MHz, DMSO-d6): δ 13.03 (brs, 1H), 8.29 (brs, 2H), 7.94 (s, 1H),7.24-7.18 (m, 2H), 6.72 (m, 1H), 6.67 (t, J=8.8 Hz, 1H), 4.90 (q, J=6.80Hz, 1H), 4.07 (m, 2H), 2.86 (m, 4H), 2.70-2.62 (m, 6H), 1.47 (d, J=6.80Hz, 3H).

(R)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoicacid

LCMS (ESI positive ion) m/z: calculated: 586.16; observed: 587.2 (M+1);HPLC purity (XB0595TF): 94.42%; Chiral HPLC purity: 98.71%; ¹H NMR (400MHz, DMSO-d6): δ 12.98 (brs, 1H), 8.30 (brs, 2H), 7.95 (s, 1H),7.25-7.19 (m, 2H), 6.73-6.68 (m, 2H), 4.91 (q, J=6.40 Hz, 1H), 4.07 (m,2H), 2.90 (m, 4H), 2.70-2.67 (m, 6H), 1.48 (d, J=6.40 Hz, 3H).

Example 62:2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-(methylamino)ethyl)acetamidehydrochloride

LCMS (ESI positive ion) m/z: calculated: 628.21; observed: 629.2 (M+1);HPLC purity (XB0595TF): 95.15%; ¹H NMR (400 MHz, DMSO-d6): δ 10.40 (brs,1H), 8.66 (brs, 2H), 8.42 (brs, 2H), 8.33 (t, J=6.0 Hz, 1H), 7.97 (d,J=1.2 Hz, 1H), 7.38 (t, J=11.60 Hz, 1H), 7.26 (m, 1H), 6.90 (t, J=8.40Hz, 1H), 6.75 (dd, J=2.00 & 3.6 Hz, 1H), 4.63 (s, 2H), 4.33 (m, 2H),3.92 (m, 2H), 3.52-3.41 (m, 6H), 3.30 (m, 2H), 3.11 (m, 2H), 3.00 (t,J=6.0 Hz, 2H), 2.56 (s, 3H).

Example 63:2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-(dimethylamino)ethyl)acetamide

LCMS (ESI positive ion) m/z: calculated: 642.23; observed: 643.3 (M+1);HPLC purity (XB0595TF): 96.98%; ¹H NMR (400 MHz, DMSO-d6): δ 8.29 (brs,2H), 7.95-7.91 (m, 2H), 7.24 (m, 2H), 6.67-6.74-6.67 (m, 2H), 4.53 (s,2H), 4.07 (t, J=6.40 Hz, 2H), 3.19 (q, J=6.40 Hz, 2H), 2.88 (m, 4H),2.71 (t, J=6.40 Hz, 2H), 2.63 (m, 4H), 2.27 (t, J=6.0 Hz, 2H), 2.07 (s,6H).

Example 64:5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4-difluoro-N-methylbenzamide

LCMS (ESI positive ion) m/z: calculated: 626.69; Observed; 627.2 (M+1);HPLC Purity (XB0595TF): 92.93%; ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (m,2H), 7.95 (s, 1H), 7.33-7.24 (m, 2H), 6.94-6.88 (m, 1H), 6.74-6.73 (m,1H), 4.09-4.06 (m, 2H), 3.53-3.49 (m, 1H), 3.33 (m, 1H), 2.97-2.56 (m,13H), 2.34-2.29 (m, 5H), and 1.90 (s, 3H).

Example 65:4-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)butanoicacid

LCMS (ESI positive ion) m/z: calculated: 600.17; observed: 601.0 (M+1);HPLC purity (XB0595TF): 90.64%; ¹H NMR (400 MHz, DMSO-d6): δ 9.90 (brs,1H), 8.42 (brs, 2H), 7.96 (s, 1H), 7.35-7.26 (m, 2H), 6.84 (t, J=9.60Hz, 1H), 6.75 (dd, J=1.6 & 3.6 Hz, 1H), 4.32 (m, 2H), 4.06 (t, J=6.40Hz, 2H), 3.91 (m, 2H), 3.51 (m, 2H), 3.29 (m, 2H), 3.07 (t, J=12.00 Hz,2H), 2.39 (m, 2H), 1.93 (t, J=6.80 Hz, 2H).

Example 66:3-(2-(4-(5-((1H-tetrazol-5-yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-5-amino-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 596.16; observed: 596.8 (M+1);HPLC purity (XB0595TF): 92.14%; ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (brs,2H), 7.95 (s, 1H), 7.28-7.24 (m, 2H), 6.98 (t, J=8.0 Hz, 1H), 6.73 (d,J=1.20 Hz, 1H), 5.48 (s, 2H), 4.10 (m, 2H), 2.95 (m, 4H), 2.78-2.67 (m,4H).

Example 67:5-amino-3-(2-(4-(2-fluoro-4-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 591.63; Observed; 592.8 (M+1);HPLC Purity (XB0595TF): 98.87%; ¹H NMR (400 MHz, DMSO-d6): δ 8.43 (s,1H), 8.30 (m, 2H), 7.95 (m, 1H), 7.24 (m, 1H), 7.01-6.73 (m, 4H), 4.99(s, 2H), 4.09-4.03 (m, 2H), 3.90 (s, 3H), 2.98-2.86 (m, 4H), and2.72-2.67 (m, 6H).

Example 68:5-amino-3-(2-(4-(2,4-difluoro-5-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 609.62; Observed; 610.2 (M+1);HPLC Purity (XB0595TF): 90.03%; ¹H NMR (400 MHz, DMSO-d6): δ 8.70 (broads, 1H), 8.49 (s, 1H), 7.94 (s, 1H), 7.32-7.07 (m, 3H), 6.72 (m, 1H),5.15 (m, 2H), 4.35-4.31 (m, 2H), 3.91-3.86 (m, 5H), 3.69 (m, 4H), and3.08 (m, 4H).

Example 69:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methyl(oxetan-3-yl)amino)ethyl)benzamide

LCMS (ESI positive ion) m/z: calculated: 636.24; observed: 637.3 (M+1);HPLC purity (XB0595TF): 97.10%; ¹H NMR (400 MHz, DMSO-d6): δ 8.34 (brs,2H), 7.96 (s, 1H), 7.60 (m, 2H), 7.24 (m, 1H), 7.03 (m, 1H), 6.73 (m,1H), 4.51 (m, 2H), 4.37 (m, 2H), 4.09 (m, 2H), 3.55 (m, 1H), 3.05 (m,4H), 2.68 (m, 6H), 2.11 (s, 3H).

Example 70:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-((2-hydroxyethyl)amino)ethyl)benzamidehydrochloride

LCMS (ESI positive ion) m/z: calculated: 610.22; observed: 611.3 (M+1);HPLC purity (XB0595TF): 96.51%; ¹H NMR (400 MHz, DMSO-d6): δ 10.25 (brs,1H), 8.72 (brs, 3H), 8.40 (brs, 2H), 7.95 (t, J=0.8 Hz, 1H), 7.72 (m,2H), 7.25 (d, J=3.2 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 6.73 (dd, J=1.6 &3.2 Hz, 1H), 5.26 (brs, 1H), 4.32 (m, 2H), 3.94 (d, J=10.8 Hz, 2H),3.68-3.56 (m, 8H), 3.16-3.03 (m, 6H).

Example 71:2-amino-N-(2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)acetamidehydrochloride

LCMS: (ESI positive ion); m/z: calculated: 596.64; Observed; 597.0(M+1); HPLC purity (XB0595TF): 94.31%; ¹H NMR (400 MHz, DMSO-d6): δ 8.31(brs, 1H), 8.22 (d, J=5.20 Hz, 1H), 7.95 (t, J=0.40 Hz, 1H), 7.24 (t,J=0.80 Hz, 1H), 6.95-6.91 (m, 1H), 6.81 (dd, J=2.80, 14.00 Hz, 1H),6.73-6.74 (m, 1H), 6.69 (dd, J=2.00, 8.80 Hz, 1H), 5.00 (brs, 1H), 4.08(t, J=6.40 Hz, 2H), 3.95 (t, J=5.60 Hz, 2H), 3.45 (q, J=5.60 Hz, 2H),3.24 (brs, 2H), 2.85 (brs, 4H), 2.70-2.67 (m, 2H), and 2.63 (m, 4H).

Example 72:(S)-2-amino-N-(2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)-3-methylbutanamidehydrochloride

LCMS: (ESI positive ion); m/z: calculated: 638.72; Observed; 639.1(M+1); HPLC purity (AM9010A3): 98.36%; ¹H NMR (400 MHz, DMSO-d6): δ 8.44(brs, 1H), 8.30 (brs, 2H), 7.94 (s, 1H), 7.23 (d, J=3.20 Hz, 1H), 6.92(t, J=9.60 Hz, 1H), 6.80-6.73 (m, 3H), 4.05-4.08 (m, 4H), 3.56-3.53 (m,1H), 3.41-3.40 (m, 1H), 2.84 (m, 4H), 2.71-2.671 (m, 3H), 2.62 (m, 3H),2.33 (m, 1H), 1.94-1.99 (m, 1H), and 0.894-0.853 (m, 6H).

Example 73: ethyl2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetate

LCMS (ESI positive ion) m/z: calculated: 600.17; observed: 601.2 (M+1);HPLC purity (XB0595TF): 96.15%; ¹H NMR (400 MHz, DMSO-d6): δ 8.31 (brs,2H), 7.96 (s, 1H), 7.24 (m, 2H), 6.72 (m, 2H), 4.85 (s, 2H), 4.16 (q,J=6.80 Hz, 2H), 4.08 (m, 2H), 2.89 (m, 4H), 2.71-2.63 (m, 6H), 1.19 (t,J=6.80 Hz, 3H).

Example 74:2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetonitrile

LCMS (ESI positive ion) m/z: calculated: 553.14; observed: 554.2 (M+1);HPLC purity (XB0595TF): 96.92%; ¹H NMR (400 MHz, DMSO-d6): δ 8.31 (brs,2H), 7.95 (d, J=0.80 Hz, 1H), 7.33 (t, J=10.80 Hz, 1H), 7.24 (d, J=3.2Hz, 1H), 6.94 (t, J=8.4 Hz, 1H), 6.73 (dd, J=1.6 & 3.2 Hz, 1H), 5.22 (s,2H), 4.09 (t, J=5.6 Hz, 2H), 2.93 (m, 4H), 2.74-2.64 (m, 6H).

Example 75:5-amino-8-(furan-2-yl)-3-(2-(4-(pyridin-4-yl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 463.15; observed: 464.1 (M+1);HPLC purity (XB0595TF): 93.77%; ¹H NMR: (400 MHz, DMSO-d6): δ 8.30 (brs,2H), 8.13 (d, J=6.40 Hz, 2H), 7.94 (d, J=0.80 Hz, 1H), 7.23 (d, J=3.60Hz, 1H), 6.77 (d, J=6.40 Hz, 2H), 6.72 (dd, J=1.6 & 3.2 Hz, 1H), 4.08(t, J=6.00 Hz, 2H), 3.23 (m, 4H), 2.71-2.67 (m, 2H), 2.58 (m, 4H).

Example 76:5-amino-8-(furan-2-yl)-3-(2-(4-(pyrimidin-4-yl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 464.15; observed: 465.1 (M+1);HPLC purity (XB0595TF): 95.02%; ¹H NMR: (400 MHz, DMSO-d6): δ 8.47 (s,1H), 8.31 (brs, 2H), 8.16 (d, J=6.40 Hz, 1H), 7.95 (s, 1H), 7.23 (d,J=2.8 Hz, 1H), 6.79 (dd, J=0.8 & 6.0 Hz, 1H), 6.73 (dd, J=1.6 & 3.2 Hz,1H), 4.08 (t, J=6.00 Hz, 2H), 3.53 (m, 4H), 2.69 (t, J=6.80 Hz, 2H),2.55 (m, 4H).

Example 79:5-amino-3-(2-(4-(6-fluoro-2-oxoindolin-5-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 535.16; observed: 536.0 (M+1);HPLC purity (XB0595TF): 82.71%; ¹H NMR (400 MHz, DMSO-d6): δ 10.26 (s,1H), 8.30 (brs, 2H), 7.95 (s, 1H), 7.24 (d, J=3.60 Hz, 1H), 6.94 (d,J=8.40 Hz, 1H), 6.73-6.74 (m, 1H), 6.60 (d, J=12.00 Hz, 1H), 4.08 (t,J=5.60 Hz, 2H), 3.39 (s, 2H), 2.84 (m, 4H), 2.72-2.63 (m, 6H).

Example 82:5-amino-3-(2-(4-(5-fluoro-2-methylpyridin-4-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 495.54; observed: 496.1 (M+1);HPLC purity (XB0595TF): 93.17%; H-NMR (400 MHz, DMSO-d6): δ 8.31 (broads, 2H), 8.08 (d, J=5.60 Hz, 1H), 7.95 (s, 1H), 7.24 (t, J=2.40 Hz, 1H),6.72-6.79 (m, 2H), 4.06-4.11 (m, 2H), 3.16 (t, J=6.00 Hz, 4H), 2.68-2.72(m, 2H), 2.62 (s, 4H), and 2.33 (s, 3H).

Example 85:5-amino-3-(2-(4-(2-fluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 568.20; observed: 569.3 (M+1);HPLC purity (XB0595TF): 92.42%; ¹H NMR (400 MHz, DMSO-d6): δ 8.31 (brs,2H), 7.95 (s, 1H), 7.24 (s, 1H), 6.92 (t, J=9.60 Hz, 1H), 6.79-6.66 (m,3H), 4.60 (s, 1H), 4.07 (m, 2H), 3.65 (s, 2H), 2.85 (m, 4H), 2.70-2.63(m, 6H), 1.17 (s, 6H).

Example 86:5-amino-3-(2-(4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 538.60; observed: 539.2 (M+1);HPLC purity (XB0595TF): 94.02%; 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (bs,2H), 7.95 (s, 1H), 7.24 (s, 1H), 7.15 (m, 2H), 6.90 (m, 1H), 6.73 (m,1H), 4.08 (t, J=6.00 Hz, 2H), 2.92 (broad s, 4H), 2.64-2.71 (m, 6H), and1.38 (s, 6H).

Example 87:5-amino-3-(2-(4-(2-fluoro-4-(3,3,3-trifluoro-2-hydroxypropoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 608.16; observed: 609.0 (M+1);HPLC purity (XB0595TF): 95.69%; ¹H NMR (400 MHz, DMSO-d6): δ 8.30 (brs,2H), 7.95 (dd, J=0.8 Hz and 1.6 Hz, 1H), 7.24 (dd, J=0.8 Hz and 3.2 Hz,1H), 6.94 (t, J=9.60 Hz, 1H), 6.85 (dd, J=2.80 Hz and 14.00 Hz, 1H),6.74-6.71 (m, 2H), 6.63 (d, J=6.80 Hz, 1H), 4.35-4.33 (m, 1H), 4.10-3.99(m, 4H), 2.86 (m, 4H), 2.70 (t, J=6.40 Hz, 2H), 2.63 (m, 4H).

Example 89:5-amino-3-(2-(4-(2,4-difluoro-5-(morpholin-2-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS (ESI positive ion) m/z: calculated: 613.64; Observed 614.2 (M+1);HPLC Purity (XB_0595TF): 96.82%; 1H-NMR (400 MHz, DMSO-d6): δ 10.95(brs, 1H), 9.71 (m, 1H), 9.51-9.49 (m, 1H), 8.40 (brs, 2H), 7.96 (s,1H), 7.36 (t, J=11.6 Hz, 1H), 7.25-7.24 (m, 1H), 6.89 (t, J=8.4 Hz, 1H),6.74-6.73 (m, 1H), 4.33-4.31 (m, 2H), 4.18-4.11 (m, 3H), 4.01-3.79 (m,2H), 3.58-3.48 (m, 2H), 3.29-3.31 (m, 4H), 3.15-2.96 (m, 6H), 2.95-2.93(m, 2H).

Example 92:5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS (ESI positive ion) m/z: calculated: 601.61; observed: 602.2 (M+1);HPLC purity (XB_0595TF): 96.09% 1H-NMR (400 MHz, DMSO-d6): δ 10.50 (s,1H), 9.92 (s, 2H), 8.40 (s, 2H), 7.96 (d, J=0.8 Hz, 1H), 7.46 (t, J=11.6Hz, 1H), 7.26-7.25 (m, 1H), 7.13-7.08 (m, 1H), 6.75-6.74 (m, 1H), 5.42(s, 1H), 5.26-5.24 (m, 1H), 4.33 (m, 2H), 3.93-3.90 (m, 2H), 3.70-3.54(m, 8H), 3.41-3.36 (m, 2H), 3.30-3.16 (m, 2H).

Example 93:5-amino-3-(2-(4-(2,4-difluoro-5-(((3R,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS (ESI positive ion) m/z: calculated: 601.61; Observed; 602.1 (M+1);HPLC Purity (XB_0595TF): 95.74%; ¹H NMR (400 MHz, DMSO-d6): δ 10.60 (s,1H), 9.83-9.75 (m, 2H), 8.41 (s, 2H), 7.97 (s, 1H), 7.41 (t, J=11.60 Hz,1H), 7.26 (d, J=3.20 Hz, 1H), 7.02 (t, J=8.40 Hz, 1H), 6.74 (q, J=1.60Hz, 1H), 5.45 (m, 1H), 5.21-5.15 (m, 1H), 4.42 (s, 2H), 3.91 (d, J=10.80Hz, 2H), 3.69-3.64 (m, 2H), 3.61 (s, 4H), 3.38 (s, 4H), 3.16 (d, J=8.80Hz, 2H).

Example 94:5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS (ESI positive ion) m/z: calculated: 601.61; Observed; 602.2 (M+1);HPLC purity (PG_AM9010.M): 91.76%; ¹H NMR (400 MHz, DMSO-d6): δ 8.31 (s,2H), 7.95 (s, 1H), 7.26-7.23 (m, 2H), 6.83 (d, J=8 Hz, 1H), 6.74 (d,J=5.6 Hz, 1H), 5.24-5.15 (m, 1H), 4.73-4.71 (m, 1H), 4.09 (t, J=6 Hz,2H), 2.91 (m, 5H), 2.73-2.63 (m, 8H), 1.92 (s, 4H), Example 97:2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-morpholinoethyl)acetamide.LCMS (ESI positive ion) m/z: calculated: 684.24; observed: 685.0 (M+1);HPLC purity (XB0595TF): 90.92%; ¹H NMR (400 MHz, DMSO-d6): δ 8.30 (brs,2H), 7.95 (d, J=0.80 Hz, 1H), 7.90 (d, J=5.60 Hz, 1H), 7.29-7.18 (m,2H), 6.76-6.70 (m, 2H), 4.55 (s, 2H), 4.08 (t, J=6.40 Hz, 2H), 3.53 (m,4H), 3.23 (t, J=6.00 Hz, 2H), 2.90 (m, 4H), 2.72 (m, 2H), 2.67 (m, 4H),2.35 (m, 6H).

Example 98:5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(morpholin-3-ylmethyl)benzamidehydrochloride

LCMS (ESI positive ion) m/z: calculated: 640.67; Observed; 641.1 (M+1);HPLC purity (XB_0595TF): 95.86%; ¹H NMR (400 MHz, DMSO-d6): δ 10.57 (s,1H), 9.50 (d, J=7.60 Hz, 1H), 9.29 (d, J=8.00 Hz, 1H), 8.64 (s, 1H),8.41 (s, 2H), 7.97 (s, 1H), 7.44 (m, 2H), 7.26 (d, J=3.20 Hz, 1H), 6.75(q, J=1.60 Hz, 1H), 4.33 (m, 2H), 3.90 (m, 4H), 3.49-3.57 (m, 8H),3.11-3.33 (m, 7H).

Example 103:5-amino-3-(2-(4-(2-fluoro-4-(((3R,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 583.62; observed: 584.2 (M+1);HPLC purity (XB0595TF): 90.29%; 1H-NMR (400 MHz, DMSO-d6): δ 10.27(broad s, 1H), 9.69-9.82 (m, 2H), 8.41 (broad s, 2H), 7.97 (m, 1H),7.26-7.27 (m, 1H), 7.05-7.10 (m, 2H), 6.87-6.90 (m, 1H), 6.75 (t, J=1.60Hz, 1H), 5.49 (m, 1H), 5.07-5.13 (m, 1H), 4.32 (d, J=5.20 Hz, 2H),3.73-3.93 (m, 2H), 3.49-3.66 (m, 2H), 3.40-3.44 (m, 3H), 3.30-3.39 (m,3H), 3.25-3.30 (m, 3H), 3.07-3.10 (m, 2H).

Example 104:5-amino-3-(2-(4-(2-fluoro-4-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 583.62; observed: 584.2 (M+1);HPLC purity (XB0595TF): 96.80%; 1H-NMR (400 MHz, DMSO-d6): δ 10.40(broad s, 1H), S 9.94 (m, 2H), 8.42 (broad s, 2H), 7.97 (s, 1H), 7.26(d, J=3.60 Hz, 1H), 7.06-7.10 (m, 2H), 6.87 (d, J=8.40 Hz, 1H),6.74-6.76 (m, 1H), 5.49 (d, J=4.00 Hz, 1H), 5.07-5.13 (m, 1H), 4.32 (s,2H), 3.90 (m, 2H), 3.62 (d, J=5.20 Hz, 2H), 3.39 (m, 6H), and 3.02-3.33(brs, 4H).

Example 105:2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-morpholinoethyl)acetamide

LCMS (ESI positive ion) m/z: calculated: 666.25; observed: 667.0 (M+1);HPLC purity (XB0595TF): 92.35%; ¹H NMR (400 MHz, DMSO-d6): δ 8.30 (brs,2H), 7.95-7.90 (m, 2H), 7.24 (dd, J=0.8 Hz and 3.2 Hz, 1H), 6.94 (t,J=10.00 Hz, 1H), 6.85-6.80 (m, 1H), 6.74-6.69 (m, 2H), 4.43 (s, 2H),4.08 (t, J=6.00 Hz, 2H), 3.53 (m, 4H), 3.22 (m, 2H), 2.90 (m, 4H),2.72-2.63 (m, 6H), 2.37-2.34 (m, 6H).

Example 106:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-morpholinoethyl)benzamide

LCMS (ESI positive ion) m/z: calculated: 636.71; observed: 637.0 (M+1);HPLC purity (XB0595TF): 92.87%; 1H-NMR (400 MHz, DMSO-d6): δ 8.29-8.32(broad s, 2H), 7.95 (s, 1H), 7.59 (m, 2H), 7.24 (s, 1H), 7.02 (m, 1H),6.73 (m, 1H), 4.07-4.10 (m, 2H), 3.55-3.57 (m, 4H), 3.33 (m, 2H), 3.04(m, 4H), 2.72 (m, 2H), 2.67-2.68 (m, 4H), and 2.51 (m, 6H).

Example 107:4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(morpholin-3-ylmethyl)benzamide

LCMS (ESI positive ion) m/z: calculated: 622.68; observed: 623.3 (M+1);HPLC purity (XB0595TF): 95.43%; 1H-NMR (400 MHz, DMSO-d6):10.58 (broads, 1H), 9.52 (d, J=8.80 Hz, 1H), 9.33 (d, J=8.40 Hz, 1H), 8.81 (d,J=5.20 Hz, 1H), 8.42 (broad s, 2H), 7.97 (s, 1H), 7.75-7.79 (m, 2H),7.26 (d, J=3.20 Hz, 1H), 7.17 (t, J=8.80 Hz, 1H), 6.74-6.75 (m, 1H),4.33 (broad s, 2H), 3.86-3.96 (m, 3H), 3.71 (s, 1H), 3.58 (t, J=11.60Hz, 2H), 3.46-3.51 (m, 4H), 3.44 (d, J=5.60 Hz, 1H), 3.41 (d, J=9.60 Hz,1H), 3.18-3.32 (m, 6H), and 3.05-3.08 (m, 1H).

Example 108:5-amino-3-(2-(4-(4-(azetidin-3-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS (ESI positive ion) m/z: calculated: 533.20; observed: 534.1 (M+1);HPLC purity (XB0595TF): 88.50%; ¹H NMR (400 MHz, DMSO-d6): δ 10.17 (brs,1H), 9.22 (brs, 1H), 9.09 (brs, 1H), 8.41 (brs, 2H), 7.96 (s, 1H), 7.25(d, J=3.56 Hz, 1H), 6.95 (d, J=8.80 Hz, 2H), 6.80 (d, J=8.92 Hz, 2H),6.73 (t, J=1.64 Hz, 1H), 4.98 (m, 1H), 4.41-4.32 (m, 4H), 3.94-3.90 (m,4H), 3.72 (m, 2H), 3.24-3.21 (m, 2H), 2.97 (m, 2H).

Example 109:(S)-5-amino-3-(2-(4-(2,4-difluoro-5-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 560.12; observed: 561.1 (M+1);HPLC purity (XB0595TF): 99.33%; ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (brs,2H), 7.95 (s, 1H), 7.45 (dd, J=9.2 Hz and 12.0 Hz, 1H), 7.29-7.24 (m,2H), 6.73 (dd, J=1.6 Hz and 3.2 Hz, 1H), 4.08 (t, J=8.0 Hz, 2H), 2.99(m, 4H), 2.80 (s, 3H), 2.73-2.67 (m, 6H).

Example 110:(R)-5-amino-3-(2-(4-(2,4-difluoro-5-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 560.12; observed: 561.0 (M+1);HPLC purity (XB0595TF): 98.18%; ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (brs,2H), 7.95 (s, 1H), 7.47-7.42 (dd, J=9.2 Hz and 12.0 Hz, 1H), 7.29-7.23(m, 2H), 6.74-6.73 (dd, J=1.6 Hz and 3.2 Hz, 1H), 4.08 (t, J=8.0 Hz,2H), 2.99-2.98 (m, 4H), 2.8 (s, 3H), 2.73-2.67 (m, 6H).

Example 113:(S)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2-(methylsulfinyl)ethyl)benzamide

LCMS (ESI positive ion) m/z: calculated: 631.68; observed: 632.2 (M+1);HPLC purity (XB0595TF): 95.04%; ¹H-NMR (400 MHz, DMSO-d6) 8.52 (d,J=2.00 Hz, 1H), 8.32 (broad s, 2H), 7.95 (s, 1H), 7.28-7.34 (m, 1H),7.20-7.25 (m, 2H), 6.73-6.74 (m, 1H), 4.07 (d, J=6.40 Hz, 2H), 3.58-3.64(m, 2H), 2.99-3.06 (m, 4H), 2.84-2.93 (m, 2H), 2.69-2.72 (m, 2H),2.65-2.69 (m, 4H), and 2.60 (s, 3H).

Example 114:(R)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2-(methylsulfinyl)ethyl)benzamide

LCMS (ESI positive ion) m/z: calculated: 631.68; observed: 632.2 (M+1);HPLC purity (XB0595TF): 96.65%; ¹H-NMR (400 MHz, DMSO-d6) δ 8.52 (d,J=2.00 Hz, 1H), 8.32 (broad s, 2H), 7.95 (s, 1H), 7.28-7.34 (m, 1H),7.20-7.25 (m, 2H), 6.73-6.74 (m, 1H), 4.07 (d, J=6.40 Hz, 2H), 3.58-3.64(m, 3H), 3.30 (m, 2H), 2.99-3.06 (m, 4H), 2.84-2.93 (m, 2H), 2.69-2.72(m, 2H), 2.65-2.69 (m, 4H), 2.60 (s, 3H).

Example 115:(S)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2-(methylsulfinyl)ethyl)benzamide

LCMS (ESI positive ion) m/z: calculated: 645.70; observed: 646.2 (M+1);HPLC purity (XB0595TF): 99.10%; ¹H-NMR (400 MHz, DMSO-d6): δ 8.13 (br s,1H), 7.85 (br s, 1H), 7.37 (t, J=9.28 Hz, 1H), 7.01-7.10 (m, 3H),6.64-6.66 (m, 1H), 4.17 (t, J=9.08 Hz, 2H), 3.87 (m, 1H), 3.72-3.78 (m,2H), 3.39-3.66 (m, 2H), 3.08-3.17 (m, 10H), 2.89-3.01 (m, 2H), and2.60-2.67 (m, 3H).

Example 116:(R)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2-(methylsulfinyl)ethyl)benzamide

LCMS (ESI positive ion) m/z: calculated: 645.7; observed: 646.1 (M+1);HPLC purity (XB0595TF): 93.418%; ¹H-NMR (400 MHz, DMSO-d6): δ 8.29 (brs, 2H), 7.94 (s, 1H), 7.22-7.32 (m, 2H), 6.95 (t, J=7.72 Hz, 1H), 6.72(d, J=1.28 Hz, 1H), 4.06 (t, J=5.92 Hz, 2H), 3.50-3.54 (m, 1H),3.06-3.11 (m, 1H), 2.96-3.02 (m, 2H), 2.86-3.00 (m, 4H), 2.78-2.86 (m,2H), 2.68-2.71 (m, 2H), 2.62 (s, 6H), and 2.47-2.50 (m, 2H).

Example 117:5-amino-3-(2-(4-(2,4-difluoro-5-(1-oxidothiomorpholine-4-carbonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 643.69; observed: 644.1 (M+1);HPLC purity (XB0595TF): 92.78%; ¹H-NMR (400 MHz, DMSO-d6): δ 7.85-7.88(m, 2H), 7.38-7.44 (m, 1H), 7.18-7.22 (m, 1H), 7.04-6.98 (m, 1H), 6.81(s, 1H), 6.65-6.71 (m, 1H), 4.35 (broad s, 1H), 4.16 (t, J=9.20 Hz, 2H),3.79-4.01 (m, 1H), 3.51-3.77 (m, 3H), 3.41-3.49 (m, 4H), 3.17-3.39 (m,2H), 2.95-3.07 (m, 4H), and 2.75-2.90 (m, 3H).

Example 118:5-amino-3-(2-(4-(2,4-difluoro-5-(1-oxidothiomorpholino)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 615.68; observed: 616.2 (M+1);HPLC purity (XB0595NHC): 93.08%; ¹H-NMR (400 MHz, DMSO-d6): δ 8.32(broad s, 2H), 7.95 (s, 1H), 7.24 (s, 1H), 7.16 (m, 1H), 6.72 (m, 2H),4.06-4.10 (m, 2H), 3.49-3.54 (m, 2H), 3.14-3.18 (m, 2H), 2.93-3.00 (m,6H), 2.82-2.85 (m, 2H), 2.67-2.72 (m, 2H), and 2.50-2.63 (m, 4H).

Example 123:(S)-4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylsulfinyl)ethyl)benzamide

LCMS (ESI positive ion) m/z: calculated: 613.17; observed: 612.0 (M−1);HPLC purity (XB0595NHC): 99.46%; ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (brs,2H), 8.09 (m, 1H), 7.95 (s, 1H), 7.58 (t, J=8.8 Hz, 1H), 7.24 (d, J=3.6Hz, 1H), 6.79-6.71 (m, 3H). 4.09 (t, J=6.0 Hz, 2H), 3.61 (q, J=6.0 Hz,2H), 3.22 (m, 4H), 3.07-3.00 (m, 1H), 2.90-2.85 (m, 1H), 2.72-2.69 (m,2H), 2.60 (m, 7H).

Example 124:(R)-4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylsulfinyl)ethyl)benzamide

LCMS (ESI positive ion) m/z: calculated: 613.17; observed: 614.1 (M+1);HPLC purity (XB0595NHC): 98.08%; ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (brs,2H), 8.09 (m, 1H), 7.95 (s, 1H), 7.58 (t, J=8.8 Hz, 1H), 7.24 (m, 1H),6.79-6.70 (m, 3H). 4.09 (t, J=6.0 Hz, 2H), 3.61 (q, J=6.0 Hz, 2H), 3.22(m, 4H), 3.05-3.00 (m, 1H), 2.90-2.85 (m, 1H), 2.72-2.68 (m, 2H), 2.60(m, 7H).

Example 125:5-amino-3-(2-(4-(2-fluoro-4-(1-oxidothiomorpholine-4-carbonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 625.17; observed: 626.0 (M+1);HPLC purity (XB0595TF): 95.09%; ¹H NMR (400 MHz, DMSO-d6): δ 8.30 (brs,2H), 7.94 (s, 1H), 7.24 (m, 2H), 6.79-6.72 (m, 3H), 4.36-4.35 (m, 1H),4.08 (t, J=6.04 Hz, 2H), 3.78-3.62 (m, 2H), 3.55-3.46 (m, 1H), 3.17 (m,4H), 2.83 (m, 3H), 2.71-2.66 (m, 3H), 2.59 (m, 4H).

Example 129:(S)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4-difluorobenzamide

LCMS (ESI positive ion) m/z: calculated: 615.62; observed: 616.1 (M+1);HPLC purity (XB0595NHC): 97.60%; ¹H-NMR (400 MHz, DMSO-d6): broad peakswere observed in 1H NMR.

Example 130:(R)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4-difluorobenzamide

LCMS (ESI positive ion) m/z: calculated: 615.62; observed: 616.2 (M+1);HPLC purity (XB0595NHC): 95.00%; ¹H-NMR (400 MHz, DMSO-d6): δ 8.32(broad m, 2H), 8.09 (s, 1H), 7.95 (s, 1H), 7.24-7.42 (m, 3H), 6.73 (s,1H), 4.84 (s, 1H), 4.60 (s, 1H), 4.32 (s, 1H), 3.96-4.08 (m, 2H), 3.56(t, J=2.80 Hz, 2H), 3.17 (t, J=6.04 Hz, 2H), 2.94 (s, 4H), 2.65-2.71 (m,6H).

Example 131:5-amino-3-(2-(4-(4-(azetidin-3-yloxy)-2-fluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-onehydrochloride

LCMS (ESI positive ion) m/z: calculated: 551.19; observed: 552.2 (M+1);HPLC purity (XB0595NHC): 90.50%; ¹H NMR (400 MHz, DMSO-d6): δ 10.33(brs, 1H), 9.33 (brs, 1H), 9.21 (brs, 1H), 8.42 (brs, 2H), 7.97 (s, 1H),7.26 (d, J=3.2 Hz, 1H), 7.05 (t, J=9.6 Hz, 1H), 6.87 (d, J=13.6 Hz, 1H),6.74-6.73 (m, 1H), 6.67 (d, J=8.4 Hz, 1H), 5.03 (s, 1H), 4.44-4.32 (m,4H), 3.93 (m, 4H), 3.60 (m, 2H), 3.43-3.06 (m, 6H).

Example 132:5-amino-3-(2-(4-(5-(azetidin-3-yloxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 569.18; observed: 570.0 (M−1);HPLC purity (XB0595TF): 94.68%; ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (brs,2H), 7.95 (s, 1H), 7.27-7.21 (m, 2H), 6.74 (s, 1H), 6.43 (t, J=8.40 Hz,1H), 5.01 (m, 1H), 4.07 (t, J=5.60 Hz, 2H), 3.71 (t, J=7.20 Hz, 2H),3.53-3.47 (m, 2H), 2.90 (m, 4H), 2.72-2.63 (m, 6H).

Example 133:(S)-5-amino-3-(2-(4-(2,4-difluoro-5-(3-(methylsulfinyl)propoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

LCMS (ESI positive ion) m/z: calculated: 618.16; observed: 617.2 (M−1);HPLC purity (XB0595NHC): 97.91%; ¹H NMR (400 MHz, DMSO-d6): δ 8.30 (brs,2H), 7.94 (s, 1H), 7.23-7.18 (m, 2H), 6.77-6.73 (m, 2H), 4.14-4.07 (m,4H), 2.89 (m, 5H), 2.77-2.55 (m, 10H), 2.05 (m, 2H).

II. BIOLOGY EXAMPLES

II.1. Assays for A2a Functional Activities

The two following assays aim at showing that the compounds of theinvention effectively inhibit A2A receptor by showing that they inhibitits functional activities.

II.1.A. Inhibition of cAMP Production in HEK Cells

Purpose. When the A2A receptor is activated, is induces the productionof cAMP. The present assay thus aims at showing that cAMP production isinhibited in HEK cells in response to their exposure to the compounds ofthe invention.

Method. HEK-293 cells with a stable transfection of A2A receptor werebought from PerkinElmer® (#ES-011-C). Cells were cultured in EMEM medium(Lonza, #BE12-611F) supplemented with 10% FBS (Lonza, #DE14-801F) and200 μg/mL of G418 (Tocris, #4131) at 37° C. and 5% CO₂. Fresh mediawithout the selection marker was added on the day immediately before theexperiment to stop selection pressure.

cAMP inhibition and antagonist IC₅₀ determination were accessed usingthe LANCE® Ultra cAMP Kit from PerkinElmer® (#TRF0262) on white halfarea 96 well plates (PerkinElmer®, #6005560). The assays were conductedin two different stimulation buffers:

-   -   a) normal with 1×HBSS (Gibco®, #141750-95), 5 mM HEPES (Lonza,        #BE17-737E), 0.1% BSA and 25 μM Rolipram and    -   b) HSA with 1×HBSS (Gibco®, #141750-95), 5 mM HEPES (Lonza,        #BE17-737E), 2% Human Serum Albumin (Sigma-Aldrich®—A1653), 30        μM of EHNA (Tocris—#1261) and 100 μM Rolipram. Stimulation        buffer b) mimics the human situation by increasing the amount of        albumin present in the assay.

Compounds of the present invention were diluted 100× in either of thebuffers depending on the assay performed. A total of 1000 cells per wellwere pre-incubated for 10 minutes with the compounds of the presentinvention before adding the corresponded EC80 of A2A agonist (3 nM ofNECA in normal buffer and 5 nM of NECA in HSA buffer) or 5 μM ofAdenosine for a total reaction time of 30 minutes. The total volume ofthe reaction was 20 μl (10 μl of cells, 5 μl of antagonist and 5 μl ofagonist). The reaction was finalized by adding 10 μl of 4×EU-cAMP tracerworking solution and 10 μl of 4× ULight-anti-cAMP working solution. TheTR-FRET signal was measured after 1 hour using a Spectramax Paradigm(Molecular Devices).

Results. As evidenced in Table 2 below, the compounds of the presentinvention inhibit the production of cAMP in response to the stimulationof A2A-overexpressing HEK cells with an A2A agonist or with Adenosine,in different conditions.

TABLE 2 IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) (3 nM NECA (5 nM NECA (5 μMAdenosine as agonist, as agonist, as agonist, Compound 0.1% BSA) 2% HSA)2.0% HSA)  1 0.6 9 511  2 0.3 17 708  4 0.5 2 49  5 0.4 8 241  6 0.5 8179  7 0.8 2 35  8a 0.6 2 25  8b 0.6 3 28  9 3.4 — — 10 2.3 14 607 112.0 — — 12 14.2 — — 13 0.6 2 63 14 0.7 11 567 15 2.6 — — 16 3.2 14 0 171.0 — — 18 1.7 85 2170 19 2.6 — — 20 1.9 352 — 21 1.6 52 1306 22 1.4 6352 23 0.6 — — 24 0.8 2 137 25 1.2 6 300 27 0.3 2 112 28 0.2 4 115 290.4 11 350 30 0.4 1 42 31 0.4 1 42 32 4.3 7 356 34 0.3 6 207 35 0.7 13378 36 0.7 8 260 37 0.8 9 398 38 0.3 9 552 39 0.8 15 719 40 0.7 7 261 410.8 14 423 42 0.4 19 332 43 0.2 1 36 44 0.5 11 127 45 0.8 3 100 47 1.8 143 48 0.1 0 9 49 0.5 16 465 50 0.3 0 13 51 0.3 0 16 52 0.3 1 26 53 — 4127 54 0.8 3 138 55 1.0 2 141 56 0.2 1 25 57 0.2 2 56 58 0.3 1 41 59 0.921 1066 60 0.8 4 240 61 0.9 15 810 62 0.5 1 21 63 0.3 1 12 64 0.6 1 3665 0.6 27 494 66 0.8 13 543 67 0.6 9 378 68 14.0 123 2697 69 0.5 5 21170 0.6 3 124 71 0.4 3 79 72 1.0 3 86 73 3.4 8 304 74 1.2 20 495 75 24100 — 76 5 151 — 77 0.5 3 158 78 0.6 — 130 79 0.3 — 77 80 0.4 — 146 81117 — — 82 0.2 — 15 83 0.4 — 212 84 0.1 — 71 85 0.4 — 220 86 0.6 — 74787 1.1 — 432 88 0.2 — 22 89 0.6 — 9 90 5.7 — 24 91 0.8 — 168 92 0.7 —388 93 0.4 — 33 95 0.7 — 37 96 0.4 — 19 97 1.1 — 30 98 0.1 — 7 99 0.5 —64 100  0.1 — 10 101  0.7 — 124 102  0.7 — 185 103  1.1 — — 104  0.5 —45 105  0.7 — 95 106  0.3 — 205 107  0.1 — 35 108  0.7 — 172 111  0.6 —91 112  0.8 — 53 113  0.4 — 37 114  0.3 — 80 116  1.2 — 245 117  329 —3162 119  0.4 — 183 120  0.4 — 123 121  0.8 — 232 122  0.8 — 187 123 1.5 — 1443 124  2.3 — 2045 125  2.6 — 3620 126  0.6 — 78 127  0.5 — 35128  0.4 — 46

II.1.B. Restoration of the Production of Pro-Inflammatory Cytokines byHuman T-Cells

Purpose. When T-cells are activated, they produce pro-inflammatorycytokines. When the A2A receptor is activated in T cells, the amount ofcytokines produced in response to stimulation of T-cells is reduced. Thepresent assay thus aims at showing that the production ofpro-inflammatory cytokines by T-cells may be restored by exposure to thecompounds of the invention.

PBMC and CD3+ T cell isolation. Venous blood from healthy volunteers,all of whom signed an informed consent approved by the Ethics Committee(FOR-UIC-BV-050-01-01 ICF_HBS_HD Version 5.0), was obtained viaImmuneHealth (Centre Hospitalier Universitaire Tivoli, La Louviere,Belgium). Mononuclear cells were collected by density gradientcentrifugation, using SepMate-50 tubes (StemCell Technologies, Grenoble,France) and Lymphoprep (Axis-shield, Oslo, Norway) according to themanufacturer's instructions. CD3+ T cells were isolated byimmunomagnetic negative selection, using the EasySep Human T CellIsolation Kit (StemCell Technologies) as per manufacturer'sinstructions. CD3+ T cells were stored in heat inactivated foetal bovineserum (hiFBS; Gibco, ThermoFisher Scientific, Merelbeke, Belgium)containing 10% DMSO in liquid nitrogen.

Human IL-2 T cell assay. Human purified CD3+ T cells were thawed andwashed twice with RPMI1640 medium (with UltraGlutamine; Lonza, Verviers,Belgium) supplemented with 1× non-essential amino acids (Lonza), 2%Pen/Strep (Lonza) and 1 mM Sodium Pyruvate (Gibco) (complete media),containing 10% hiFBS. The cells were suspended either in complete mediacontaining 20% hiFBS or in 100% heat inactivated human serum (hiHS;Sigma-Aldrich, Diegem, Belgium). Cells were activated by adding anti-CD3and anti-CD28 coated microbeads (Dynabeads human T-activator CD3/CD28;Life Technologies, Paisley, UK), suspended either in complete mediacontaining 20% hiFBS or in 100% hiHS. Selective A_(2A) R agonistCGS-21680 (Sigma-Aldrich; stock solution of 10 mM in DMSO) was added ata final assay concentration of 0.5 or 5 μM. Serial dilutions of thecompounds of the present invention were prepared and added to the wells.The cells were placed in a 37° C. humidified tissue culture incubatorwith 5% CO₂ for 72 hours. After 72 hours, supernatants were sampled andIL-2 was quantified using the IL-2 (human) AlphaLISA Biotin-FreeDetection Kit (AL333F; Perkin-Elmer, Zaventem, Belgium), according tothe manufacturer's instructions.

Results. Addition of the A2A selective agonist CGS-21680 to CD3+ T cellsdecreases the amount of cytokines produced in response to stimulationwith anti-CD3 and anti-CD28 coated microbeads. The compounds of thepresent invention dose-dependently restore the production ofpro-inflammatory cytokines IL2 in CGS-21680-treated human T cells, withpotencies indicated in Table 3 below.

TABLE 3 IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) (500 nM (500 nM (5000 nM(5000 nM CGS-21680 CGS-21680 CGS -21680 CGS-21680 as agonist, asagonist, as agonist, as agonist, Compound 10% FBS) 50% HSA) 10% FBS) 50%HSA) 31 2.1 5.4 8.3 14 35 0.6 0.5 3.9 84 39 1.0 12 5.3 150 50 1.0 2.24.3 28 32 — — — 28 43 — — — 51 1 — — — 120 44 — — — 33 49 — — — 61 4 0.3— — 63 2 0.9 — — 18

II.1.C. Restoration of the Production of Pro-Inflammatory Cytokines inHuman Whole Blood

Preparation of test tubes. Tubes containing selected stimulants (SEB,LPS, zymosan, anti-CD3/CD28) and TruCulture medium were purchased fromMyriad RBM (catalogue numbers respectively 782-001124, 782-001087,782-001259 and 782-001125) and A2a agonists (CGS-21680 and NECA) andwere added and the tubes directly frozen at −20° C. until use in thecell culture experiments.

Compound 7 was dissolved in DMSO at 10 mM and then dilutions were madewith TC medium. Solutions were microscopically inspected to rule out thepresence of particles. Freshly-prepared Compound 7-containing solutionswere added to thawed TC tubes containing stimulants and 1 μM CGS-21680,where appropriate.

Cell culture. Blood was drawn from healthy donors from the pre-testeddonor pool of HOT Screen GmbH (age: 20-65 years, both sexes).Heparinized fresh peripheral whole blood (1 mL) from 3 healthy donorswas added to thawed TC tubes and incubated in a heating block at 37□Cfor 24 hours (LPS and zymosan stimulations), or 48 hours (SEB andanti-CD3/CD28 stimulation). At the end of the culture period, seraplasfilters were inserted for harvesting of the supernatants. Supernatantswere carefully collected, mixed, aliquoted and frozen at −20° C.

Mediators quantification. Cytokines and chemokines released in TCsupernatants were measured using Human Cytokine MAP A panel for Luminexassays. The following mediators were analysed: GM-CSF, IFNg, IL-2, IL-3,IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-18, MCP-1, MIP-1a, MIP-1b,TNF-a, TNF-b.

Data analysis. To assess the biological activity of CGS-21680 and NECA,alterations of cytokine and chemokine secretion in TC supernatantsinduced by increasing doses of A2A agonists were analyzed. Thepercentage change of the concentrations of soluble mediators (SM) wascalculated for each stimulation condition as follows:

% change=100×[SMTC+A2A agonist]/[SMTC−A2A agonist].

To assess the biological activity of Compound 7, the Compound 7-inducedrestoration of cytokine and chemokine secretion inCGS-21680-supplemented TC to baseline levels (i.e. TC stimulationwithout supplementation of CGS-21680) was analyzed. The rescue ofcytokine secretion was estimated by calculating the percentage controlfor each stimulation condition of whole blood TC as follows:

% control=100×[SMTC+CGS+Compound 7]/[SMTC-CGS−Compound 7].

Results. LPS, zymosan, SEB and anti-CD3/CD28 induce the secretion ofseveral cytokines and chemokines in whole blood cell cultures. Thebiological activity of two A2A agonists (CGS-21680 and NECA) on wholeblood cell cultures stimulated with LPS, zymosan, SEB or anti-CD3/CD28was assessed. Both agonists dose-dependently altered the secretion ofseveral cytokines and chemokines. The effect was reproducible across thethree tested donors, although the extent of alterations differed betweenindividuals.

When 1 μM CGS-21680 or NECA were added to LPS- or zymosan-stimulatedwhole blood cultures, the effect on the release of both pro- andanti-inflammatory cytokines reached a plateau. In particular, levels ofpro-inflammatory cytokines IFNg and TNFa were reduced by more than 50%,while levels of anti-inflammatory cytokines IL-8 and IL-10 were doubled.

The ability of Compound 7 to revert alterations of cytokine andchemokine secretion induced by CGS-21680 on whole blood cell culturesstimulated with LPS, zymosan, or anti-CD3/CD28 was assessed. As shown inFIGS. 1A and 1B, Compound 7 dose-dependently restored the alterations ofcytokine and chemokine secretion induced by CGS-21680, with a fullrescue achieved with concentrations of 100-1000 nM of compound,depending on the conditions tested. The effect was reproducible acrossthe three tested donors, although the extent of alterations differedbetween individuals.

Secretion of IFNg, TNFa, IL-8 and IL-10 in LPS- and zymosan-stimulatedwhole blood TC was mostly affected by CGS-21680 treatment, and was fullyrescued by 40-100 nM Compound 7.

II.2. Modulation of pCREB

II.2.A. Modulation of pCREB in human immune cells

Purpose. The A2A receptor is known to mediate CREB phosphorylation. Thepresent assay aims at showing that the compounds of the inventioneffectively inhibit A2A receptor by showing that CREB phosphorylationmay be inhibited by exposing human immune cells to compounds of theinvention.

Method. Venous blood from healthy volunteers, all of whom signed aninformed consent approved by the Ethics Committee (FOR-UIC-BV-050-01-01ICF_HBS_HD Version 5.0), was obtained via ImmuneHealth (CentreHospitalier Universitaire Tivoli, La Louviere, Belgium). Peripheralblood cells were treated with A2AR agonists CGS-21680 or NECA(Sigma-Aldrich, Diegem, Belgium), and a serial dilution of compounds ofthe present invention (all used stock solutions at 10 mM in DMSO). Alldilutions were prepared in RPMI1640 medium (with UltraGlutamine; Lonza,Verviers, Belgium), and cells were incubated with compounds in a 37° C.humidified tissue culture incubator with 5% CO₂. After stimulation,cells were fixed and permeabilized, followed by intracellular stainingusing mouse anti-human pCREB antibodies (Clone J151-21; BD Biosciences)at room temperature. Data were acquired using an LSRFortessa flowcytometer (BD Biosciences) and analyzed using FlowJo software (FlowJo,LLC, Ashland, Oreg.).

Results. The compounds of the present invention were found to inhibitA2A-mediated CREB phosphorylation. For example, compound 4 exhibits anIC₅₀ of 20 nM in peripheral blood lymphocytes activated by NECA, asshown in FIG. 2 .

II.2.B. Modulation of pCREB Ex Vivo in Mice

Purpose. The A2A receptor is known to mediate CREB phosphorylation. Thepresent assay aims at showing that the compounds of the inventioneffectively inhibit A2A receptor by showing that CREB phosphorylationmay be inhibited in mice by dosing compounds of the invention to mice.

Method. Compound 7 was formulated in 10% DMSO, 10% solutol, 80% water,pH 3 to obtain a homogeneous solution. Volume was calculated in order toadminister the final dose in 100 μl per oral (PO). BALB/cAnNCrl femalemice were purchased from Charles River Laboratories. Mice were orallytreated with a single dose of A2A receptor antagonist. At the specifictime point, animals were anesthetized with IP injection of 200 μl ofketamine 10%/xylazine 0.1% in PBS and blood was collected viaretro-orbital bleeding in EDTA tubes. 45 μl of blood/well was dispensedin a master block. A2A receptor agonist NECA (Tocris) was prepared atconcentration of 3 M in RPMI 1640 (Lonza) supplemented with medium 2%Penicillin/Streptomycin (Lonza) and 50% M 2-Mercaptoethanol (Sigma), and50%1 was added to the wells and incubated for 45 minutes in a 37° C.humidified cell culture incubator with 5% CO2. The final concentrationof DMSO in the assay was 0.125%. Cells were fixed by adding 1 ml ofpre-warmed Lyse/Fix buffer (BD Biosciences) in each well, carefullymixed and incubated for 10 minutes in a 37□C humidified cell cultureincubator with 5% CO2. Cells were pelleted by centrifugation at 600×gfor 5 minutes. After a wash with 1 ml of DPBS with Ca2+Mg2+ (Lonza),cells were permeabilized with 200%1 of ice-cold Perm Buffer II (BDBiosciences) and incubated for 30 minutes on ice. Duringpermeabilization, cells were transferred to a 96-well U-bottom plate.Cells were pelleted and washed twice with FACS buffer composed by PBS(Lonza), 0.1% BSA (VWR), 2 mM EDTA (Ambion). The FACS staining wasperformed resuspending the cells in FACS buffer containing Fc block(CD16/CD32 Monoclonal Antibody (93), eBioscience); after 5 minincubation at room temperature the antibody mix was added and cellsincubated for 1 hour at room temperature. Cells were washed with FACSbuffer and resuspended in the same for acquisition at BD Fortessa (BDBiosciences).

Data obtained with flow cytometry were analyzed with FlowJo 10.4software. MFI (median fluorescence intensity) of our marker of interest,pCREB, was evaluated, normalized by the respective DMSO control (ratio)and reported in graph. Dose-response data were analyzed with GraphPadPrism 7.0 software using nonlinear regression applied to a sigmoidaldose-response model. Data were acquired using an LSRFortessa flowcytometer (BD Biosciences) and analyzed using FlowJo software (FlowJo,LLC, Ashland, Oreg.).

Results. Compound 8a demonstrates full inhibition of A2A signalingpathway at CD4+ T cells 30 minutes after p.o. at a dose of 0.1 mg/Kg(Table 4). More than 70% of inhibition of A2A signaling pathway is stillobserved at the dose of 1 mg/Kg 12 hours after dosing. Similar data areobtained for the CD8+ T cells (Table 5).

TABLE 4 Activity of Compound 8a 30 minutes after oral administration.CREB phosphorylation assessed in CD4+ T cells Treatment Mean %inhibition P value vs Group-1 Group-1 Vehicle 0.0 — Group-2 Compound 8a28.3 0.0005 (0.01 mg/kg) Group-3 Compound 8a 84.0 <0.0001 (0.03 mg/kg)Group-4 Compound 8a 100.7 <0.0001 (0.1 mg/kg) Group-5 Compound 8a 102.1<0.0001 (0.3 mg/kg) Group-6 Compound 8a 101.0 <0.0001 (1 mg/kg)

TABLE 5 Activity of Compound 8a 12 hours after oral administration. CREBphosphorylation assessed in CD4+ T cells Treatment Mean % inhibition Pvalue vs Group-1 Group-1 Vehicle 0.0 — Group-2 Compound 8a 40.0 0.0003(0.1 mg/kg) Group-3 Compound 8a 43.2 0.0001 (0.3 mg/kg) Group-4 Compound8a 72.9 <0.0001 (1 mg/kg) Group-5 Compound 8a 75.2 <0.0001 (3 mg/kg)

II.3. Cytotoxicity Assay

Purpose. The activation of the A2A receptor provides animmunosuppressive signal that inhibit cytotoxicity. The present assayaims at showing that the compounds of the invention effectively inhibitA2A receptor by showing that cytotoxicity may be increased by exposureto compounds of the invention.

Method. A cytotoxicity assay was conducted to assess theantigen-specific cytotoxic activity of OT-I CD8 cells towards OVA-pulsedtarget cells and the effect of the compounds of the present invention toalleviate A2AR mediated inhibition of Cytotoxicity: OT1 cells wereisolated from the spleens of C57BL/6-Tg(TcraTcrb)1100Mjb/Crl mice(Charles River). OT1 cells were primed with 1 ug/ml OVA peptide(Ovalbumin (257-264) chicken (57951-1MG), Sigma Aldrich), in thepresence of 5 μM CGS-21680 (Sigma-Aldrich) and increasing concentrationsof compounds of the present invention, for 3 days in a 37° C. humidifiedtissue culture incubator with 5% CO2. On day 3 all the cells were pooledand counted. For the cytotoxicity assay on day 3, Panc02 (target cells)were pulsed with 1 μg/ml OVA. Target cells and non-pulsed Panc02 cells(non-target bystander) were labelled with CFSE (C1157 (ThermoFisher))and CellTrace™ Far Red Cell Proliferation Kit (C34564, ThermoFisher)respectively, according to manufacturer instructions. The stimulatedOT-1 cells were added as effector cells in a 10:1 effector to targetratio. The co-culture reaction was incubated at 37° C. humidified tissueculture incubator with 5% CO₂. After 24 hrs cells were washed andstained with Live/dead fixable violet dead cell staining kit (MolecularProbes, L34955). Cytotoxic-killing of target cells was then measured bymonitoring the change in the ratio of living target cells to non-targetcells by flow-cytometry (MACSQuant® Analyzer 10—Miltenyi Biotec).

The % cytotoxicity is calculated as follows: %Cytotoxicity=(1−R1/R²)*100

-   -   wherein R¹=(% of Target cells)/(% non-target cells)*100 in        presence of effector cells and R²=(% of Target cells)/(%        non-target cells)*100 in absence of effector cells.

Results. Addition to the media of A2A agonist CGS-21680 leads to adecrease of the cytotoxicity, which can be reduced dose-dependently bycompounds of the present invention (Table 6). This is for exampleillustrated in FIG. 3 for compounds 4 and 31 of the invention.

TABLE 6 Compound IC₅₀ (nM) Compound 31 12.6 Compound 4 25.7 Compound 7108.5 Compound 8a 107.4 Compound 77 663.9

III. PHARMACOKINETIC EXAMPLES

III.1. Determination of Permeability and Efflux in Caco-2 Cells

Purpose. As mentioned in the introduction, the compounds of theinvention have to exhibit a limited, if any, CNS penetrance, in order toavoid deleterious side effects that can occur if these compoundspenetrate significantly into the brain.

The present assay aims at showing that the compounds of the invention donot have any significant CNS penetrance by showing that they aresubstrates of transporters that efflux them from brain.

Indeed, it is well known in the art that xenobiotics that are substratesof transporters such as P-Glycoprotein are not efficient in penetratingthe Blood-Brain Barrier, and are thus less effective in the CentralNervous System (Alfred H. Schinkel, “P-Glycoprotein, a gatekeeper in theblood-brain barrier”, Advanced Drug Delivery Reviews 36 (1999) 179-194).

The present assay thus aims at showing that the compounds of the presentinvention are substrates to such transporters present in the Caco-2 cellline and thus do not cross the Blood-Brain Barrier.

Material. The transport buffer (TB, pH 7.4) used in the study is Hank'sBuffered Saline Solution (HBSS, Gibco, Cat #14025-076) with 10 mM HEPESat pH 7.4. Fetal bovine serum (FBS) (Corning, Cat #Corning-35-076-CV, orother vendors), Minimum Essential Media (MEM) (Gibco, Cat #41500-034) aswell as its supplements are purchased from Invitrogen (Carlsbad, Calif.,USA). Caco-2 cell line (Cat #HTB-37) is purchased from the ATCC(Rockville, Md., USA). The organic solvents used in the study arepurchased from Sigma Aldrich (St. Louis, Mo., USA).

Preparation of Working Solutions. For reference compounds (fenoterol,propranolol and digoxin) and test compounds, 0.4 mM intermediatesolutions are prepared by diluting 10 mM or other appropriateconcentrations of DMSO stock solutions with DMSO. 2 μM dosing solutionsfor reference compounds and test compounds are prepared by spiking theappropriate volume of intermediate solution to TB with and without 1 μMZosuquidar. The final concentration of DMSO is no more than 1% (v/v).

Caco-2 Cell Culture. Caco-2 cells are grown in MEM supplemented with 2mM L-glutamine, 10% FBS, 100 U/mL penicillin-G and 100 μg/mLstreptomycin. The cells are incubated at 37° C., 5% CO₂ and relativelysaturated humidity. After reaching 80-90% confluency, the cells aregently detached with 0.05% trypsin-EDTA solution. Cells at passage 30-50are seeded on the 96-well BD insert system (Cat #359274) at the densityof 1×105 cells/cm2 and cultured for 21-28 days with medium changed every4-5 days.

Transport Procedures. TB and dosing solutions were pre-warmed to 37° C.before transport assay. The cell monolayer was washed twice with HBSScontaining 10 mM HEPES. For A-B (apical to basolateral) directionaltransport assay, 75 μL dosing solution is added to the apical well. Filleach basolateral well with 250 μL TB. For B-A (basolateral to apical)directional transport assay, 250 μL of dosing solution is added to thebasolateral well after filling each apical well with 75 μL TB. Testcompound(s) and digoxin are tested at 2 μM in the presence or absence of1 μM zosuquidar bidirectionally in duplicate. Atenolol and propranololare tested at 2 μM in the absence of zosuquidar in A to B direction induplicate. The plates are incubated for 120 minutes at 37° C. with 5%CO₂ and saturated humidity. The time zero samples are generated bymixing 50 μL initial dosing solution of test compound or referencecompound with 100 μL TB and 250 μL quench solution (acetonitrile (ACN)or other appropriate solvent with internal standard(s), based on thebioanalytical method development). At 120 minutes, 150 μL of solution iscollected from each A-B receiver well followed by addition of 250 μLquench solution to get A-B receiver sample. And for other samples (A-Bdonor, B-A donor and receiver), 50 μL of solution is collected from eachcorresponding well followed by addition of 250 μL quench solution and100 μL TB. All samples are vortex-mixed and centrifuged at 3220 g for 20minutes. Subsequently, supernatant is diluted with ultra pure water forLC-MS/MS analysis. The concentrations of test compound in all samplesare determined by LC-MS/MS and expressed as peak area ratio of analyteto internal standard.

The concentration of samples is expressed using the peak area ratio ofAnalyte to Internal Standard (Analyte/IS).

The apparent permeability coefficient (Papp) is calculated using thefollowing equation:

P _(app) =V _(R)/(Area*Time)*(C _(R) /C ₀)

-   -   wherein V_(R) is the solution volume in the receiver chamber        (0.075 mL on the apical side, 0.25 mL on the basolateral side);        Area is the surface area for the transport, i.e. 0.0804 cm2 for        the area of the monolayer; Time is incubation time, expressed in        seconds, 2 h=2×3600 s; C₀ is the initial concentration in the        donor chamber; C_(R) is the final concentrations in receiver        chamber.

The efflux ratio is calculated using the following equation:

Efflux ratio=Papp(A−B)/Papp(B−A)

-   -   where Papp (A−B) and Papp (B−A) are the Papp values of compound        in Apical to Basolateral and Basolateral to Apical directional        transport, respectively.

Results. Compounds are generally considered to be P-Glycoproteinsubstrates when the value of efflux ratio is >3. Compounds of thepresent invention typically have efflux ratios >3, as evidenced in Table7 below.

TABLE 7 Compounds Efflux ratio  1 48  2 28  3 4  4 123  5 67  6 59  71871  8a 207  8b 300  9 8 10 24 24 117 25 472 27 187 30 3 31 28 32 32934 192 35 26 39 110 40 25 43 164 44 69 45 41 46 30 47 329 48 166 49 9750 38 51 469 52 34 54 24 55 205 56 1751 57 2196 62 23 63 264 64 60 661012 67 15 68 108 69 201 70 53 71 28 72 21 74 4 77 43 78 45 79 47 80 14982 3 83 29 84 24 85 5 86 5 87 7 88 19 89 456 90 86 91 195 92 101 94 17395 137 96 118 98 53 99 13 100  66 101  81 102  91 103  20 104  20 107 680 108  191 111  583 112  605 113  374 114  403 116  421 117  12 119 31 120  33 121  90 122  349 123  120 124  54 125  127 126  83 128  419

III.2. Determination of the Concentration A2a Antagonists in Brain andCerebrospinal Fluid Compared to Plasma

Purpose. The present assay aims at showing that the compounds of theinvention do not have any significant CNS penetrance by determining theconcentration of these compounds in brain and cerebrospinal fluid (CSF)compared to plasma.

Method. 7-9 weeks old female Balb-c mice (obtained from SLAC LaboratoryAnimal Co. Ltd., Shanghai, China or SIPPR-B&K Laboratory Animal Co.Ltd., Shanghai, China) were dosed orally at a dose of 10 mg/kg, as a1.00 mg/mL suspension in 10% DMSO+10% solutol+80% water, adjusted to pH3-4 (homogenous opaque suspension).

Animals were fasted at least 12 hours prior to the administration. Allanimals had access to Certified Rodent Diet (Catalog #M01-F, SLACLaboratory Animal Cl. Ltd., Shanghai, China) ad libitum 4 hours postdosing. Serial bleeding (about 30 μL blood per time point) wereperformed from submadibular or saphenous vein. Those samples weretransferred into prechilled microcentrifuge tubes containing 2 μL ofK2EDTA (0.5M) as anti-coagulant and placed on wet ice for furthertreatment. Immediately after blood collection, the whole brain washarvested immediately at the designed time points. At selectedtimepoints post-dose, CSF was collected from cisterna magna.

Blood samples were processed for plasma by centrifugation atapproximately 4° C., 3000 g 15 min within half an hour of collection.Plasma samples were stored in polypropylene tubes, quick frozen over dryice and kept at −70° C. until LC/MS/MS analysis. Brain samples wereweighed, rinsed in cold distilled water to remove blood, and homogenizedusing pre-cooled water at the ratio of 1:4 (1 g brain used 4 mL water).And the brain homogenization was kept at −70° C. until LC/MSMS analysis.CSF was quick frozen over dry ice and kept at −70° C. until LC/MS/MSanalysis.

Results. For example, for compound 4 of the invention, no measurablequantity could be found in brain or CSF of mice in these conditions.

Individual and Mean Concentration of Example 4 after PO Administration(10 mg/kg) are provided in Table 8 below.

TABLE 8 Time (h) Mouse 1 Mouse 2 Mouse 3 Mean Plasma Concentration(ng/mL) 0.500 576 995 765 779 Brain Concentration (ng/g) 0.500 <15 16.9<15 <16 CSF Concentration (ng/mL) 0.500 <3 <3 <3 <3 Brain/Plasma Ratio0.500 <0.026 0.0169 <0.020 <0.021 CSF/Plasma Ratio 0.500 <0.005 <0.003<0.004 <0.004

III.3. Determination of the CNS Activity by a Locomotion Assay

Purpose. In addition to adenosines immune-suppressive effects, it hasalso been established that adenosine modulates neuronal functions viaits interaction with A2AR in the central nervous system. Thisinteraction mediates part of the dopamine pathway which is involved inmovement. Prevention of this signalling in the brain, by highly brainpenetrant A2AR antagonist compounds such as Preladenant (originallysynthesised for prevention of Parkinson's disease), have been shown toinduce hyper locomotion in animals. This could potentially pose aproblem with compounds that were purposed for Parksons's therapy (likePrelandenant) that are being repurposed for cancer immunotherapy.

The present assay aims at showing that the compounds of the invention donot have any significant CNS activity by using a method published byHodgson et al. (J. Pharma. And Exp. Thera. 2009). The principle of thisassay is that CGS21680, a brain penetrant A2AR specific adenosineanalogue, induces immobility (hypolocomotion) within minutes aftersubcutaneous (s.c.) injection in mice. Therefore a mouse treated with abrain penetrant A2AR antagonist prior to treatment with CGS21680 willprevent hypolocomotion.

Preladenant, a reference brain penetrant compound, was compared to thecompounds of the present invention at various concentrations per os (PO)for their effect on CGS21680 induced immobility.

Methods. Compounds were administered 30 min prior to CGS21680 andlocomotion was monitored over a 30 min period. Mice were scored (Table9) for immobility, using a range of scores described in Table 10.

Results. CGS21680, after 30 min, induced complete immobility whenadministered alone at 1 mg/kg (s.c.). Preladenant inhibited CGS21680induced immobility when administered P.O. at 10 mg/kg, while thecompounds of the present invention failed to completely preventimmobility when administered at equivalent doses. These data support thePK data from brain and spinal fluid, confirming that compounds of thepresent invention have decreased brain penetrance and CNS activitycompared to Preladenant.

TABLE 9 Compounds of the present invention have decreased brainpenetrant activity Compound Dose (PO) Score* Vehicle n/a ++++ Compound 410 mg/kg +++ Compound 7 10 mg/kg +++ Preladenant  1 mg/kg + Preladenant10 mg/kg 0 *Score observed in at least 60-100% of mice for 30 minutes, n= 3-5 mice per group

TABLE 10 Locomotion scoring Score Description 0 Fully active-alert,running cage perimeter, rearing up, stretch, climbing, digging, gnawing,feeding + Active-alert, localized running, digging, rear up, stretching,gnawing ++ Activity limited-intermittent localized walking, gnawing,lethargic, some hunching +++ Activity severelyabrogated/sleep-intermittent rearing up and gnawing, no walking,lethargic, eyes partly closed, hunched ++++ No activity/deep sleep-nomovement, eyes closed, shivering

1. A compound of Formula (I)

or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹represents 5- or 6-membered heteroaryl or 5- or 6-membered aryl, whereinheteroaryl or aryl groups are optionally substituted by one or moresubstituent selected from C₁-C₆ alkyl and halo; R² represents 6-memberedaryl or 6-membered heteroaryl, wherein heteroaryl or aryl groups areoptionally substituted by one or more substituent selected from halo,alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl,alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl,alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl,alkylsulfonimidoyl, carbonylamino, sulfonylamino and alkylsulfonealkyl;said substituents being optionally substituted by one or moresubstituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl,aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonylalkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl; or theheteroaryl or aryl groups are optionally substituted with twosubstituents that form together with the atoms to which they areattached a 5- or 6-membered aryl ring, a 5- or 6-membered heteroarylring, a 5- or 6-membered cycloalkyl ring or a 5- or 6-memberedheterocyclyl ring; each of which are optionally substituted by one ormore substituent selected from oxo, halo, hydroxy, cyano, alkyl,alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, amino carbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)amino carbonyl,alkylamino alkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.
 2. Thecompound according to claim 1, of Formula (Ia)

or a pharmaceutically acceptable salt or solvate thereof, wherein: X¹and X² represent each independently C or N; R¹ is absent when X¹ is N;or when X¹ is C, R¹ represents H, halo, alkyl, heterocyclyl, alkoxy,cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl,hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl,aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino,sulfonylamino or alkylsulfonealkyl; wherein R¹′ is optionallysubstituted by one or more substituents selected from oxo, halo,hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl,hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl,heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylamino alkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl; R²′ representsH, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy,carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl,heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl,heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino,or alkylsulfonealkyl; wherein R^(2′) is optionally substituted by one ormore substituent selected from oxo, halo, hydroxy, cyano, alkyl,alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)amino carbonyl,alkylamino alkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl; or R^(1′) andR^(2′) form together with the atoms to which they are attached a 5- or6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or6-membered cycloalkyl ring or a 5- or 6-membered heterocyclyl ring;wherein each group is optionally substituted by one or more substituentselected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde,heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl; R^(3′) isabsent when X² is N; or when X² is C, R^(3′) represents H or halo;R^(4′) represents H or halo; and R^(5′) represents H or halo.
 3. Thecompound according to claim 2, of Formula (Ia-1)

or a pharmaceutically acceptable salt or solvate thereof.
 4. Thecompound according to claim 2, of Formula (Ia-1a)

or a pharmaceutically acceptable salt or solvate thereof, wherein:R^(1″) represents an alkyl or heterocyclyl group substituted by one ormore group selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl,aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylamino alkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.
 5. Thecompound according to claim 2, of Formula (Ia-1b)

or a pharmaceutically acceptable salt or solvate thereof, wherein:R^(1′) represents H or halo; and R^(2″) represents an alkyl orheterocyclyl group substituted by one or more group selected from oxo,halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl,hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl,heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylamino alkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.
 6. Thecompound according to claim 2, of Formula (Ia-1c) or (Ia-1d)

or a pharmaceutically acceptable salt or solvate thereof, wherein:R^(1′) represents H or halo; R^(T) represents H or halo; R^(1i) andR^(1ii) represent each independently hydrogen, hydroxy, alkyl, alkenyl,heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl,aminoalkyl, alkylaminoalkyl, dialkylamino alkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylamino alkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkylsulfoxidealkyl or alkylsulfonealkyl; and R^(2i) and R^(2ii)represent each independently hydrogen, hydroxy, alkyl, alkenyl,heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl,aminoalkyl, alkylaminoalkyl, dialkylamino alkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkylsulfoxidealkyl or alkylsulfonealkyl.
 7. The compound according toclaim 2, of Formulae (Ia-2) or (Ia-3)

a pharmaceutically acceptable salt or solvate thereof.
 8. The compoundof claim 1, selected from the group consisting of:3-(2-(4-(4-((1H-1,2,3-triazolo-4yl)methoxy-2fluorophenyl)piperazine-1-yl)ethyl)-5-amino-(8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-2(3H)-one;5-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)methyl)-1,3,4-oxadiazol-2(3H)-one;5-amino-3-(2-(4-(3-fluoropyridin-4-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetamide;(S)-5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(luran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(R)-5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)-piperazin-1-yl)ethyl)-8-(ftiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(iiran-2-yl)thiazolo[5,4-e] [1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(iiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(iiran-2-yl)thiazolo[5,4-e] [1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-8-(furan-2-yl)-3-(2-(4-(4-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;2-(4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)phenoxy)aceticacid;2-(4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)phenoxy)acetamide;5-amino-3-(2-(4-(4-(2,3-dihydroxypropoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(4-(2-aminoethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzamide;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-methylbenzamide;5-amino-8-(iiran-2-yl)-3-(2-(4-(4-(2-morpholinoethoxy)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(4-(2-(dimethylamino)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzenesulfonamide;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-methylbenzenesulfonamide;5-amino-8-(furan-2-yl)-3-(2-(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-8-(furan-2-yl)-3-(2-(4-(4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzamide;5-amino-8-(furan-2-yl)-3-(2-(4-(3-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(2-oxo-2-(piperazin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(ftiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(piperidin-4-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(piperazine-1-carbonyl)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(piperazin-1-ylsulfonyl)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(methylsulfonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-aminoethyl)-3-fluorobenzamide;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylamino)ethyl)benzamide;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3-fluorobenzamide;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-3-fluorobenzamide;2-(4-(4-(25-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)aceticacid;2-(4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3,5-difluorophenoxy) acetic acid;2-(4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoicacid;(S)-2-(4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoicacid; 2-(4-(4-(25-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-2-methylpropanoicacid; 3-(4-(4-(25-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)propanoicacid;4-(4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)butanoicacid;2-(3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,6-difluorophenoxy)acetic acid; 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetic acid;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorobenzoicacid;2-((2-(4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl) amino)acetamide;2-((2-(4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)(methyl)amino)acetamide;5-amino-3-(2-(4-(2-fluoro-4-(piperidin-4-yloxy) phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl) thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(pyrrolidin-3-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(iiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;3-(2-(4-(4-((1H-1,2,4-triazol-3-yl)methoxy)-2-fluorophenyl)piperazin-1-yl)ethyl)-5-amino-8-(iuran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;2-(4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-(methylamino)ethyl)acetamide;2-(4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-(dimethylamino)ethyl)acetamide;2-(4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-aminoethyl)acetamide;(R)-2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoicacid;2-(4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)acetamide;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-methyl-N-(2-(methylamino)ethyl)benzamide;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3-fluoro-N-methylbenzamide;(R)-4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl) ethyl)piperazin-1-yl)-N-(1-(dimethylamino)propan-2-yl)-3-fluorobenzamide;2-(4-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-methyl-N-(2-(methylamino)ethyl)acetamide;2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-2-methylpropanoicacid;(S)-2-(5-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoic acid;(R)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoic acid; 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-(methylamino)ethyl)acetamide;2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-(dimethylamino)ethyl)acetamide;5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4-difluoro-N-methylbenzamide;4-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)butanoic acid;3-(2-(4-(5-((1H-tetrazol-5-yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-5-amino-8-(iuran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2,4-difluoro-5-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methyl(oxetan-3-yl)amino)ethyl)benzamide;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-((2-hydroxyethyl)amino)ethyl)benzamide;2-amino-N-(2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c] pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl) acetamide;(S)-2-amino-N-(2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)-3-methylbutanamide;ethyl 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c] pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy) acetate;2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetonitrile; 5-amino-8-(furan-2-yl)-3-(2-(4-(pyridin-4-yl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-8-(furan-2-yl)-3-(2-(4-(pyrimidin-4-yl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(6-fluoro-2-oxoindolin-5-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(S-methylsulfonimidoyl)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4-difluorobenzamide;5-amino-3-(2-(4-(5-fluoro-2-methylpyridin-4-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(3,3,3-trifluoro-2-hydroxypropoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-5-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2,4-difluoro-5-(morpholin-2-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2,4-difluoro-5-(morpholin-3-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2,4-difluoro-5-(((3R,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(S)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(R)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-morpholinoethyl)acetamide;5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(morpholin-3-ylmethyl)benzamide;5-amino-3-(2-(4-(2-fluoro-4-(morpholin-3-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(morpholin-2-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(((3R,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 2-(4-(4-(25-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-morpholinoethyl)acetamide;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-morpholinoethyl)benzamide;4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(morpholin-3-ylmethyl)benzamide;5-amino-3-(2-(4-(4-(azetidin-3-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(S)-5-amino-3-(2-(4-(2,4-difluoro-5-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(R)-5-amino-3-(2-(4-(2,4-difluoro-5-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2,4-difluoro-5-(((1s,4s)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2,4-difluoro-5-(((1r,4r)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (S)-5-(42-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2-(methylsulfinyl)ethyl)benzamide;(R)-5-(4-(2-(5-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2-(methylsulfinyl)ethyl)benzamide;(S)-5-(42-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2-(methylsulfinyl)ethyl)benzamide;(R)-5-(4-(25-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2-(methylsulfinyl)ethyl)benzamide;5-amino-3-(2-(4-(2,4-difluoro-5-(1-oxidothiomorpholine-4-carbonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2,4-difluoro-5-(1-oxidothiomorpholino)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(R)-5-amino-3-(2-(4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(iiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(S)-5-amino-3-(2-(4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(iiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(((1s,4s)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(((1r,4r)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (S)-4-(42-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylsulfinyl)ethyl)benzamide;(R)-4-(4-(25-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylsulfinyl)ethyl)benzamide;5-amino-3-(2-(4-(2-fluoro-4-(1-oxidothiomorpholine-4-carbonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(2-fluoro-4-(1-oxidothiomorpholino)phenyl)piperazin-1-yl)ethyl)-8-(fiiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(S)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(ftiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(R)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(ftiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(S)-5-(42-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4-difluorobenzamide;(R)-5-(4-(25-amino-8-(fliran-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4-difluorobenzamide;5-amino-3-(2-(4-(4-(azetidin-3-yloxy)-2-fluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;5-amino-3-(2-(4-(5-(azetidin-3-yloxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(iiran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;(S)-5-amino-3-(2-(4-(2,4-difluoro-5-(3-(methylsulfinyl)propoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;and pharmaceutically acceptable salts or solvates thereof.
 9. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt or solvate thereof, and at least onepharmaceutically acceptable carrier.
 10. Medicament comprising acompound according to claim 1, or a pharmaceutically acceptable salt orsolvate thereof.
 11. A compound of claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, for use in the treatment and/orprevention of cancer.
 12. The compound for use according to claim 11,wherein the cancer is selected from breast, carcinoid, cervical,colorectal, endometrial, glioma, head and neck, liver, lung, melanoma,ovarian, pancreatic, prostate, renal, gastric, thyroid and urothelialcancers.
 13. A compound according to claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, for use as A2A inhibitor. 14.Process for manufacturing a compound of Formula (Ia) according to claim2, or a pharmaceutically acceptable salt or solvate thereof,characterized in that it comprises the coupling between amineintermediate of Formula (A)

and intermediate of Formula (B)

wherein Y represents halo, alkylsulfonyloxy having 1 to 6 carbon atomsor arylsulfonyloxy having 6 to 10 carbon atoms.
 15. A method formodulating A2A activity comprising administering the compound of claim 1to a subject in need thereof.
 16. A method for treating cancercomprising administering to a subject in need thereof a compound ofFormula (I)

or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹represents 5- or 6-membered heteroaryl or 5- or 6-membered aryl, whereinheteroaryl or aryl groups are optionally substituted by one or moresubstituent selected from C₁-C₆ alkyl and halo; R² represents 6-memberedaryl or 6-membered heteroaryl, wherein heteroaryl or aryl groups areoptionally substituted by one or more substituent selected from halo,alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl,alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl,alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl,alkylsulfonimidoyl, carbonylamino, sulfonylamino and alkylsulfonealkyl;said substituents being optionally substituted by one or moresubstituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl,aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)amino carbonyl,alkylamino alkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl; or theheteroaryl or aryl groups are optionally substituted with twosubstituents that form together with the atoms to which they areattached a 5- or 6-membered aryl ring, a 5- or 6-membered heteroarylring, a 5- or 6-membered cycloalkyl ring or a 5- or 6-memberedheterocyclyl ring; each of which may be optionally substituted by one ormore substituent selected from oxo, halo, hydroxy, cyano, alkyl,alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, amino carbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)amino carbonyl,alkylamino alkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.
 17. A methodfor treating cancer, comprising administering to a patient in needthereof the compound according to claim
 2. 18. A method for treatingcancer, comprising administering to a patient in need thereof thecompound according to claim
 8. 19. A method for modulating A2A activity,comprising administering to a patient in need thereof the compoundaccording to claim 8.